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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from peer reviewed journal

Data source

Reference
Reference Type:
publication
Title:
Reproductive an developmental toxicity of the test chemical
Author:
Gingell et al.
Year:
1991
Bibliographic source:
J. AM. TOX. 1991

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
The developmental toxicity effect of test chemical in Fischer 344 rats was assessed in a two generation of rat.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Reference substance name:
Alcohols, C9-11, branched and linear, ethoxylated
Cas Number:
68439-46-3
IUPAC Name:
Alcohols, C9-11, branched and linear, ethoxylated
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report):Alcohols, C9-11, branched and linear, ethoxylated ( Neodol 91-6)
- Molecular formula : Unspecified
- Molecular weight: Unspecified
- Substance type:Organic

Test animals

Species:
rat
Strain:
Fischer 344
Details on test animals or test system and environmental conditions:
TEST ANIMALS:
Source: Parents: Charles River Breeding Laboratories.
F1 Generation: produced as the result of mating of the P generation rats during the conduct of the study.
Age: 4-7 weeks of age

Administration / exposure

Route of administration:
dermal
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- M/F ratio per cage: one male rat per one female rat.
Duration of treatment / exposure:
not specified
Frequency of treatment:
Daily
Duration of test:
133 Days (F1 generation)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 100, 250 mg/kg bw/d (1, 10, 25% w/v, 0.5 mL/kg)
Basis:
nominal conc.
No. of animals per sex per dose:
total ;400

F0:240
Control: 30 males, 30 females
1% w/v: 30 males, 30 females
10% w/v: 30 males, 30 females
25% w/v: 30 males, 30 females

F1:160
Control: 20 males, 20 females
1% w/v: 20 males, 20 females
10% w/v: 20 males, 20 females
25% w/v: 20 males, 20 females
Control animals:
yes
Details on study design:
Details of controls: Control animals received water, based on its weekly body weight

Examinations

Maternal examinations:
All rats were observed for viability at least twice daily throughout the study.
Pups were observed daily for mortality and physical abnormalities.
No mortalities were observed in the F0 generation
5 deaths were noted in the F1 generation (1 in control, 4 in different treatment groups).
Ovaries and uterine content:
No data available
Fetal examinations:
Litter size, sex of pups, and number of live and stillborn pups. Pups were observed daily for mortality and physical abnormalities
Statistics:
Organ weights, LDH-X activity, litter size, sex ratio, and survival index were compared to controls by a one-tailed Dunnett’s t-test at p < 0.05.
Fertility indices were analyzed by a one-tailed Fisher’s exact test. Mating indices were analyzed by Chi-square with continuity correction.
Sperm counts and survival indices were analyzed by the nonparametric Kruskal-Wallis test
Indices:
No data available
Historical control data:
No data available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Both male and female rats in the 10% and 25% groups had dry flaking skin. Discoloration of the application sites was noted in all treated rats, including the controls.

Dermal irritation (if dermal study):
no effects observed
Description (incidence and severity):
Individual skin irritation scores for all rats in all dose groups was zero (0) throughout the F0 and F1 generations.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the F0 adults, significantly lower (p < 0.05) body weights of the 25% group were observed only during certain intervals when compared to the control .In the F1 adults, body weights of males in the 25% group were lower but were only statistically significant (p < 0.05) at days 21, 28, and 35 during the dosing period. Body weights of the 25% females were slightly lower from days 14-1 19 during the dosing period when compared to the controls.
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 specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In the F0 generation, the absolute and relative organ weights were comparable to the controls.
In the F1 generation, organ weight differences were observed sporadically. Since there were no macroscopic or microscopic histopathologic changes in any internal organs, these organ weight changes are considered to be of no toxicologic significance. There were no significant differences in testicular histology for any treated rats compared to the controls in these two generations.
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
not specified
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
There were no compound-related effects on fertility index and mean gestational length of the F0 and F1 females.
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxic effects:no effects. Remark: There were no compound-related effects on maternal body weights at any dose groups during the gestational and lactational periods in the F, and F, generations

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Remarks on result:
other: No toxic effects were observed

Maternal abnormalities

Abnormalities:
not specified
Localisation:
not specified

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
In the F1 and F2 pups, there were no differences in organ weight or morphology.
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects. Remark: no dose-related trend in sex ratio alteration was seen at the 250 mg/kg/day

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: no observed adverse effects
Remarks on result:
other: No developmental toxic effects were observed

Fetal abnormalities

Abnormalities:
not specified
Localisation:
other: not specified

Overall developmental toxicity

Developmental effects observed:
not specified
Treatment related:
not specified

Any other information on results incl. tables

EFFECT ON OFFSPRING IN TWO-GENERATION DERMAL STUDY

 

Concentration(%)

0

1

10

25

0

1

10

25

 

F1 GENERATION

F2 GENERATION

Mean live litter size

 

 

 

 

 

 

 

 

Day 0

8.2

9.5

7.8

6.3

6.8

8.3

8.0

8.3

Day 28

7.6

8.6

6.9

5.9

6.6

8.0

7.4

7.6

Sex ratio (M/F)

 

 

 

 

 

 

 

 

Day 4

0.85

0.67

0.89

0.82

0.85

0.79

1.08

1.00

Body weights

(g)a

 

 

 

 

 

 

 

 

Day 1

5.4

5.4

5.4

5.6

5.6

5.6

5.7

5.7

Day 28

59.1

59.1

58.5

60.6

55.9

57.9

59.3

57.8

Survival index (%)

 

 

 

 

 

 

 

 

Day 1

100

99

99

98

98

99

98

97

Day 28b

100

100

95

99

98

100

98

98

 

aAdjusted for litter size.

bExpressed as a%of the pups alive on day 4 after culling to 10 pups per litter

 

Applicant's summary and conclusion

Conclusions:
No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 250mg/kg bw/day. When male and female rats were treated with test chemical via dermal application
Executive summary:

The two generation reproduction toxicity study of test chemical was performed on male and femaleFisher 344 rats. A group of 30 weanling rats of each sex were dermally exposed to 1 mL/kg bw test chemical at concentrations of 0, 1, 10 or 25% w/v three times a week except during the mating periods. This treatment equals exposure levels of about 0,10, 100 or 250 mg/kg bw/d. Clinical observations were made daily during treatment and mating periods and twice daily during gestation and lactation.

Male and female body weights were taken weekly up to the time of mating and females weekly during gestation and lactation. F0 females were weighed weekly after day 28 of lactation. Pups were weighed as a litter on days1,4, 7,21, and 28 of lactation and individually on day 28 of lactation. After 119 days of dosing the F0 rats and133days of dosing the F1 rats, females were housed with males of the same treatment group. In the first week of the F1 mating period,30males and30females in each dose group were paired. Only proven males with positive matings were used in the following 2 weeks. In the first week of the F1 mating period, 20 males and 20 females in a 1: 1 ratio were cohabitated, and sibling or half-sibling matings were avoided. Only proven fertile males were used for the subsequent mating.

Each male rat in the F0 and F1generations was killed after breeding, and the left testis was used for enumeration of sperm heads and measurement of lactate dehydrogenase isozyme (LDH-X) activityLitters were caged with their mothers for at least 21 days after birth.Atparturition, the following observations were made: litter size, sex of pups, and number of live and stillborn pups. Pups were observed daily for mortality and physical abnormalities. On day4of lactation, any litter with more than 10 pups was culled to 10 by using a table of random numbers. Individual litter weights of the F0 and F1 generations were determined. Gross necropsies were performed on all F0 and F1 parents and selected F1 and F2 pups (5/sex/dose group). Histopathologic examinations included all reproductive organs, all lesions in F0 parents, and all tissues of the selected F1 pups. Organ weights and histopathologic examination of the F1reproductive organs, liver, spleen, heart, kidney, and lung of the F1 parents, and selected F2 pups in the highest dose group and the vehicle control group were performed. No mortalities were observed in the F0 generation Deaths were noted in the F1 generation(1in control,4in different treatment groups). At necropsy, the posterior pharynx of each rat was filled with moist, finely ground, and compacted food material that occluded the laryngeal opening of the rats. Death apparently was caused by asphyxiation and was not considered to be compound related. Both male and female rats in the 10% and25%groups had dry flaking skin. Discoloration of the application sites was noted in all treated rats, including the controls. Individual skin irritation scores for all rats in all dose groups was zero (0) throughout the F0 and F0 generations. In the F0 adults, significantly lower (p < 0.05) body weights of the 25% group were observed only during certain intervals when compared to the control .In the F1 adults, body weights of males in the 25% group were lower but were only statistically significant (p < 0.05) at days 21, 28, and35during the dosing period. Body weights of the 25% females were slightly lower from days14-1 19during the dosing period when compared to the controls. In theF0parental males, testis weights were not affected by the treatment, whereas the number of sperm per testis and per gram of testis were significantly lower in the 25% group when compared to the controls Values of LDH-X enzyme activity in all treated groups were comparable to the control. However, in the F1 parental males, all the noted parameters in all dose groups were comparable to the controls. The lower numbers of sperm in the testis of the high-dose F1 males were within the normal historical control range for this laboratory. Therefore, the difference is not considered to be a treatment-related effect. In the F0 generation, the absolute and relative organ weights were comparable to the controls. In the F1 generation, organ weight differences were observed sporadically. Since there were no macroscopic or microscopic histopathologic changes in any internal organs, these organ weight changes are considered to be of no toxicologic significance. There were no significant differences in testicular histology for any treated rats compared to the controls in these two generations. Mating indices were73.3%, 83.3%, 83.3%,and93.3%in the F0 generation and65.0%, 70.9%.82. 1%, and83.8%in the F1 generation of the 0, 1, 10, and 25% groups, respectively. The incidences appeared to be higher in the treated groups than the control in both generations but were not significantly different from the control group by Chi-square test with continuity correction. The lower mating performance of the control rats is within the historical range for the Fischer strain. There were no apparent morphologic differences in any affected rats to explain their apparent infertility. There were no compound-related effects on fertility index and mean gestational length of the F0 and F1 females. The fertility indices were77.3%, 64.0%. 76.0%,and53.6%in the F0 generation and88.5%,67.9%, 87.5%,and77.4%in the F1 generation of the 0, 1, 10, and 25% groups, respectively. Mean gestational length in all dose groups in the F0 and F1 generations was approximately 22 days. No compound-related effects on litter size, survival index, sex ratio, or body weights of pups in the F1 and F2 generations were observed during lactation. There were no compound-related effects on maternal body weights at any dose groups during the gestational and lactational periods in the F1and F2generations. There was no compound-related effect on development of the pups. Eye opening was observed at approximately16.1-16.9days for the F,pupsand 17.2-17.6 days postnatally for the F, pups in all dose groups. In the F1 and F2 pups, there were no differences in organ weight or morphology. HenceNo Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 250mg/kg bw/day. When male and femalerats were treated withtest chemical via dermal application.