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Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Although this study was not conducted in accordance with current international guidelines or GLP, in accordance with REACH Annex XI, Section 1.1.2, the study was conducted under the same scientific principles of the toxicity to reproduction test and adequate documentation of the study is provided. The study is therefore considered adequate for fulfilling this endpoint and for risk assessment purposes.

Data source

Reference
Reference Type:
publication
Title:
The inhalation toxicity of phenylglycidyl ether: reproduction, mutagenic, teratogenic, and cytogenetic studies
Author:
James B. Terrill
Year:
1982
Bibliographic source:
Terrill, J.B., Lee, K.P., Culik, R. and Kennedy, G.L. (1982) The inhalation toxicity of phenylglycidyl ether: Reproduction, mutagenic, teratogenic and cytogenetic studies. Toxicology and Applied Pharmacology, 64:204-212.

Materials and methods

Principles of method if other than guideline:
This study was conducted before OECD Guideline 416 (Two-generation Reproduction Toxicity Study) was adopted. Although this study was not conducted in accordance with OECD 416, the methods and analyses used can be considered as being equivalent to OECD 413 as described herein.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2,3-epoxypropyl phenyl ether
EC Number:
204-557-2
EC Name:
2,3-epoxypropyl phenyl ether
Cas Number:
122-60-1
Molecular formula:
C9H10O2
IUPAC Name:
2-(phenoxymethyl)oxirane
Details on test material:
PGE purity was 99.6 % with trace amounts of phenol and diglycidyl ether as determined by gas chromatography.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Sprague-Dawley (ChR-CD, Charles River Breeding Labs) rats were used for this study. Standard laboratory chow (Purina Rat Chow, Ralston Purina Co., St. Louis, Mo.) and water were available ad libitum during nonexposure periods.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Details on exposure:
The test atmosphere was generated by syringe-driving unheated liquid into a tube furnace. The furnace tube (2 in. i.d. x 24 in. length, stainless steel) was constructed in such a way that the wall temperature of the delivery tube and the pure nitrogen stream (10 L/min) were the same temperature, 310 degrees celsius. The nitrogen-PGE atmosphere was delivered directly to the exposure chamber.
Exposures were run in 5 cubic metre chambers. Satisfactory chamber temperature (< 32 degrees celsius) and oxygen levels were maintained by the 2000 L/min inlet air velocity.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber atmospheres were monitored for PGE and phenol by UV analysis of impinger samples. Typically a 1 L/min sample was drawn through 15 ml of 0.1 N NaOH in 50:50 ethanol:water for 10 minutes. At 5 ppm (v/v), this solution has an absorbance of 0.4 (1 cm cell) at lambda max of 270nm. Phenol has a lambda max at 288 nm and can be detected at 5 % or greater of the PGE concentration (minimum sensitivity: 1 ppm of PGE, phenol >/= 0.05 ppm; 5 ppm, phenol >/= 0.25 ppm; 12 ppm, phenol >/= 0.6 ppm) using the analytical procedure.
Samples were taken hourly and the final concentrations were calculated on a time-weighted-average (TWA) basis (+/- σ).
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
1.75 ± 0.2 ppm TWA
Basis:
analytical conc.
Reproduction Phase
Remarks:
Doses / Concentrations:
5.84 ± 6.8 ppm TWA
Basis:
analytical conc.
Reproduction Phase
Remarks:
Doses / Concentrations:
11.2 ± 2.8 ppm TWA
Basis:
analytical conc.
Reproduction Phase
Control animals:
yes

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:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

A decrease in the number of pregnancies resulting from mating to males exposed at the highest level (11 ppm) the first week post exposure suggested a treatment relationship, but all other reproductive data appeared normal and it is concluded that this isolated finding was not related to exposure to PGE.

Effect levels (P0)

Dose descriptor:
NOAEC
Effect level:
11 ppm (analytical)
Based on:
test mat.
Sex:
male/female

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Description (incidence and severity):
A single pup in the 2 ppm treatment (F1) displayed an abnormal hair pattern (curly hair) which was an isolated occurrence and was not considered to be an effect of PGE exposure. 20 % of this pups progeny also displayed this abnormal hair pattern.
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Effect levels (F1)

Dose descriptor:
NOAEC
Generation:
F1
Effect level:
11 ppm (analytical)
Based on:
test mat.
Sex:
male/female

Results: F2 generation

Effect levels (F2)

Dose descriptor:
NOAEC
Generation:
F2
Effect level:
11 ppm (analytical)
Based on:
test mat.
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Growth of treated rats as indicated by body weight data, was unaffected by PGE, and no change in parental mortality profiles was produced. The fertility of PGE treated male rats was normal; pups were delivered in normal numbers and showed normal survival during the lactation period (Table 1). The lowered lactation indices in the two higher groups during the second week reflect the failure of an automatic watering system over one weekend, resulting in increased pup death in these two groups. However, evaluation of the data remaining derived from the PGE-treated male rats revealed an absence of any treatment-related changes, supporting the assumption that the lowered progeny survival was a reflection of water-deprivation stress rather that chemical treatment. Progenies from all groups were generally free of gross structural anomalies and showed normal growth over the lactation period.

One F1a male pup, derived from the second week of mating with a male rat exposed to 2 ppm, exhibited a patch of curly hair, especially pronounced on the dorsal surface. This rat was subsequently mated with females of the same treatment group and week (not the same litter), and a proportion (approximately 20 %) of the offspring had curly hair.

Gross pathology of these rats was unremarkable.

The results of the interim sacrifice are presented in Table 3. The number of litters with early resorption, indicative of a dominant lethal response, was not increased among the PGE-treated rats. The postimplantation loss, defined as the number of implantations minus the number of viable fetuses, in the control group ranged from 0.5 to 1.4, in the low level from 0.4 to 1.0, in the medium level from 0.4 to 1.1, and in the high level from 0.6 to 1.6.Statistically significant differences were observed in week 5 where groups treated with either 2 or 11 ppm PGE had a higher number of corpora lutea, implantations, and viable fetuses than the controls. This isolated finding is probably the result of biological variation rather than treatment. Also, the number of females pregnant in week 1 in the 11 ppm PGE group was significantly lower that that of the controls. Again, the lack of a consistent reduction makes the significance of the finding questionable, but the dose-time relationship may suggest some interference with reproduction capability.

One male rat from each of the three treatment groups (eight rats per group) showed testicular atrophy upon histopathological examination. The gross appearance and weight of these testes did not suggest significant damage and the functional capacity for reproduction was demonstrated in these rats. Statistical analysis, while limited by the group size, supports the lack of significance.

Indices of fertility in the second matings (F1a and F2a) were atypically low (30 -40 %) in all groups. Reproductive parameters, along with progeny numbers, growth, and survival were unaffected by previous PGE exposure. No evidence of a dominant lethal response was obtained. Gross pathologic examination of F2a pups were unremarkable.

Table 1. Reproductive Performance and Viability of the F1a Generation

Treatment

Mating weeka

Fertility index

No. pups/litter

No. born alive (%)

Lactation indexb(%)

Control

1

20/24

10.5

99.1

97.7

2

17/23

11.6

98.1

97.2

3

20/24

11.2

99.2

96.9

4

18/24

11.3

100

62.5

5

19/24

10.5

99.1

71.6

6

17/24

8.7

97.7

95.4

2 ppm

1

18/24

11.5

96.4

95.8

2

17/24

11.6

96.6

97.5

3

20/24

11.3

98.0

96.2

4

18/24

9.1

100

55.0

5

19/24

10.6

100

84.4

6

20/24

12.0

100

90.6

6 ppm

1

16/24

12.3

99.1

87.5

2

19/24

10.4

98.2

32.0c

3

20/24

10.7

100

81.3

4

20/24

10.2

99.2

75.6

5

19/24

10.6

100

83.0

6

21/24

11.3

100

89.9

11 ppm

1

10/24

10.0

95.7

100

2

18/24

10.3

99.2

32.2c

3

18/24

9.8

98.1

84.4

4

19/24

9.3

100

88.2

5

19/24

9.2

100

82.6

6

20/24

10.4

100

95.2

a - Fertility index is the number of matings (of 24) which resulted in pregnancy. During week 2 in the control group, 1 female died.

b - Litter size reduced to eight pups/litter by the killing of additional pups at birth. Lactation index is number of pups alive at day 21 divided by the number retained at day 0.

c - Failure of automatic watering system over weekend resulted in poor survival of progeny in these two groups.

Table 2. Body Weights of F1a Progeny during Lactation

Treatment Group (ppm)

Lactation Day (Body Weight (g))a

0

7

21

Males

Females

0

6.6 (6.4-6.7)

16.7 (15.4-18.9)

51 (47-53)

47 (43-50)

2

6.5 (6.2-6.7)

16.9 (15.6-19.3)

49 (44-52)

47 (41-50)

6

6.4 (6.1-6.6)

14.2 (13.2-15.6)

45 (43-48)

44 (42-48)

11

6.6 (6.3-7.0)

16.0 (9.0-22.0)

49 (38-52)

46 (36-55)

a - Numbers indicate mean values from all 6 weeks collected by group; numbers in parentheses represent ranges on a weekly basis.

Table 3. Summary and Analysis of Dominant-Lethal Data

Week

PGE (ppm)

No. pregnant of eight mated

Fertility index (% pregnant)

No. corpora lutea

No. implantationsa

Preimplantation lossa(corpora lutea implantations)

No. litters with early resorptions (%)

No. litters with late resorptions

No. viable fetusesa

Postimplantation lossa(No. implantations-No. viable fetuses)

1

0

8

100.0

12.3

11.3

1.0

3 (38)

0 (0)

10.8

0.5

2

6

75.0

12.0

11.5

0.5

4 (67)

0 (0)

10.5

1.0

6

7

87.5

11.1

10.7

0.4

5 (71)

0 (0)

9.6

1.1

11

3

37.5↓b

12.3

12.3

0.0

2 (67)

0 (0)

11.7

0.7

2

0

7

87.5

13.6

13.0

0.6

4 (57)

0 (0)

12.3

0.7

2

7

87.5

13.1

12.4

0.7

2 (29)

1 (14)

11.9

0.6

6

7

87.5

12.1

10.3

1.8

2 (29)

3 (43)

9.4

0.9

11

6

75.0

13.5

12.2

1.3

4 (67)

0 (0)

11.3

0.8

3

0

8

100.0

13.3

12.3

1.0

4 (50)

1 (13)

11.4

0.8

2

7

87.5

13.6

12.6

1.0

2 (29)

1 (14)

11.9

0.7

6

8

100.0

12.5

11.9

0.6

3 (38)

0 (0)

11.3

0.6

11

7

87.5

11.9

11.4

0.4

3 (43)

0 (0)

10.6

0.9

4

0

8

100.0

11.6

9.0

2.6

3 (38)

0 (0)

8.4

0.6

2

6

75.0

13.7

9.5

4.2

3 (50)

0 (0)

9.0

0.5

6

7

87.5

12.0

10.0

2.0

3 (43)

0 (0)

9.4

0.6

11

7

87.5

10.4

9.4

1.0

5 (71)

0 (0)

7.9

1.6

5

0

7

87.5

10.1

8.7

1.4

3 (43)

0 (0)

7.4

1.4

2

7

87.5

12.3↑

10.9↑

1.4

3 (43)

0 (0)

10.4↑

0.4

6

8

100.0

11.3

9.8

1.5

3 (38)

0 (0)

9.4

0.4

11

7

87.5

12.3↑

11.4↑

0.9

3 (43)

0 (0)

10.9↑

0.6

6

0

7

87.5

15.6

14.0

1.6

4 (57)

1 (14)

13.0

1.0

2

8

100.0

14.5

11.8

2.8

4 (50)

0 (0)

10.8

1.0

6

8

100.0

14.8

12.5

2.3

3 (38)

0 (0)

11.6

0.9

11

8

100.0

14.3

12.6

1.6

5 (63)

0 (0)

11.4

1.2

a - Mean for litters

b - ↓ Significantly lower than control by Fisher's exact test; ↑ significantly higher than control by Mann Whitney U test.

Applicant's summary and conclusion

Conclusions:
Rats exposed to atmospheres of up to 11 ppm PGE showed no significant abnormalities in reproductive evaluations.