Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Endpoint waived due to existence of study equivalent/similar to OECD 414; Palmer et al. (1974)

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
A study equivalent/similar to OECD 414 (Prenatal Developmental Toxicity Study; Palmer et al. 1974) was performed on a substance utilised in this dossier for Read-Across purposes (sodium dodecyl sulphate), therefore negating the need to commisssion an additional toxicity to reproduction study. As per Regulation (EC) 1907/2006, Annex VII, Part 8.7.1, Column 2 - the study/ies do(es) not generally need to be conducted if:
a pre-natal developmental toxicity study (Annex IX, 8.7.2: Pre-natal developmental toxicity study, one species, most appropriate route of administration, having regard to the likely route of human exposure - B.31 of the Commission Regulation on test methods as specified in Article 13(3) or OECD 414) is available.
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A study equivalent/similar to OECD 414 (Prenatal Developmental Toxicity Study; Palmer et al. 1974) was performed on a substance utilised in this dossier for Read-Across purposes (alcohol sulphate), therefore negating the need to commission an additional toxicity to reproduction study. As per Regulation (EC) 1907/2006, Annex VII, Part 8.7.1, Column 2 - the study/ies do(es) not generally need to be conducted if:

a pre-natal developmental toxicity study (Annex IX, 8.7.2: Pre-natal developmental toxicity study, one species, most appropriate route of administration, having regard to the likely route of human exposure - B.31 of the Commission Regulation on test methods as specified in Article 13(3) or OECD 414) is available.

Effects on developmental toxicity

Description of key information

NOAEL for maternal toxicity: 300 mg/kg bw/day; NOAEL for developmental toxicity > 600 mg/kg bw/day; equivalent/similar to OECD 414; Palmer et al, 1974.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1974
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH - Refer to Section 13.2 for read-across justification document
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Remarks:
Study pre-dates GLP
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: East Anglian Rabbitries, Colchester, England
- Age at study initiation: Not reported
- Weight at study initiation: Not reported
- Fasting period before study: Not reported
- Housing: Individually in metal cage with wire mesh floor and maintained at 18 ± 2 ºC and 50 ± 5 % RH.
- Diet (e.g. ad libitum): Ad lib (SG-1 diet)
- Water (e.g. ad libitum): Ad lib
- Acclimation period: Not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 2 ºC
- Humidity (%): 50 ± 5 % RH
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): Not reported

IN-LIFE DATES: From: To: Not reported
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Solutions were prepared daily as a series of graded aqueous solutions so that within each study animals in all groups were dosed orally by intragastric intubation at a standard volume. Control animals were dosed with water.

DIET PREPARATION
- Rate of preparation of diet (frequency): N/A
- Mixing appropriate amounts with (Type of food): N/A
- Storage temperature of food: N/A

VEHICLE
- Justification for use and choice of vehicle (if other than water): N/A
- Concentration in vehicle: N/A
- Amount of vehicle (if gavage): Not reported
- Lot/batch no. (if required): N/A
- Purity: N/A
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
N/A
Details on mating procedure:
- Impregnation procedure: Co-housed - details not reported
- Proof of pregnancy: Observation of coitus
Duration of treatment / exposure:
Dosing commenced on Day 6 (Day 0 = confirmation of mating) and continued up to and including Day 18
Frequency of treatment:
Daily
Duration of test:
29 days
Dose / conc.:
0.2 mg/kg bw/day (nominal)
Dose / conc.:
2 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
600 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Females: 13
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: 0.2 and 2.0 mg/kg/day were chosen as likely maximum human intake estimates (from detergents). 300 and 600 mg/kg/day were investigated to provoke obvious adverse effects, the pattern of which would help in assessing the relevance of any marginal differences that might occur at the lower tested concentrations.
- Rationale for animal assignment (if not random): Not reported
- Other: N/A
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule: 'Regularly'

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): N/A

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): N/A

POST-MORTEM EXAMINATIONS: Yes
- Conducted on all animals either at death (during the test) or at test termination.

OTHER: N/A
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: N/A
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: No
Statistics:
Differences in mean values were statistically analysed by non-parametric methods (Wilcoxon test) since litter values rarely, if ever, follow a normal (Gaussian) distribution; in all analyses the litter was considered as the basic sample unit.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Toxic effects were generally associated with a principal disturbance of the gastrointestinal tract. Affected rabbits showed diarrhoea, anorexia, weight loss and cachexia prior to death (moribund animals were killed for humane reasons); total litter loss (abortion and/or total resorption) tended to occur as a secondary consequence of the primary effect on the mother.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
Mortality was only observed in the highest two concentration groups; 1/13 and 11/13 in the 300 and 600 mg/kg/day test groups, respectively.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Retarded weight gain observed in the 300 mg/kg/day test group and weight loss observed in the 600 mg/kg/day.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Details on results:
Strong toxic effects were observed in rabbits treated at the highest test concentration including; diarrhoea, anorexia, weight loss and cachexia prior to death. 11/13 individuals died during the course of the study in the 600 mg/kg/day test group, in comparison to 2/13 and 1/13 in the control and 300 mg/kg/day test groups, respectively.
Number of abortions:
no effects observed
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:
no effects observed
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed
Other effects:
not examined
Details on maternal toxic effects:
At the maternally toxic dose of 600 mg/kg/day, there was an increase in foetal loss and reduced litter size, due almost entirely to total litter losses. These factors were deemed to be a secondary consequence of the maternal reaction to the test item, indicated by the fact that among the rabbits bearing young at termination litter parameters were comparable to the control group.
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
mortality
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not examined
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
A higher incidence of rabbit pups with extra ribs in the 300 mg/kg/day treatment group was observed. The degree of incidence was within the normal historical laboratory range so this effect was deemed to be non-significant.
Visceral malformations:
no effects observed
Other effects:
not examined
Details on embryotoxic / teratogenic effects:
The incidence of major, minor, visceral and skeletal abnormalities was unaffected in rabbit pups. A statisticaly significant increase in the number of pups with extra ribs was observed in the 300 mg/kg/day test group. The degree of incidence was within the normal historical laboratory range so this effect was deemed to be non-significant.
Key result
Dose descriptor:
NOAEL
Effect level:
> 600 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested
Abnormalities:
no effects observed
Developmental effects observed:
no

Table 2       Summary of maternal performance

 

Observation

Number of animals at dosage

Control

0.2 mg/kg/day

2.0 mg/kg/day

300 mg/kg/day

600 mg/kg/day

Mated

13

13

13

13

13

Died

2

0

1^

1

11

Non-pregnant

1

1

2

1

0

Total litter loss

0

1

0

2

0

With viable young

10

11

10

9

2

Bodyweight change

-

retarded gain

-

retarded gain

loss

 

Table 3       Group mean litter data

 

Dosage

(mg/kg/day)

Number of litters ^

Litter size (of viable young)

Embryonic deaths

Implantations

Corpora lutea

Embryonic loss %

Litter weight

(g)

Foetal weight

(g)

Pre-implantation

Post-implantation

0

A=B=10

7.3

0.5

7.8

10.7

27.2

4.3

295.7

43.1

0.2

A=12

B=11

7.1

7.7

0.8

0.4

7.8

8.1

9.2

9.5

12.8

12.5

13.9

6.1

-

331.3

-

43.5

2.0

A=B=10

9.0

1.3

10.3

10.7

3.8

12.8

332.6

37.1

300

A=11

B=9

7.7

9.4

2.4

0.6

10.1

10.0

10.8

10.8

6.3

6.8

22.7

5.6

-

357.3

-

37.9

600

A=B=2

8.0

2.0

10.0

11.0

9.1

18.2

297.2

37.1

^ Mean A = includes all surviving animals showing evidence of implantation, including those with total litter loss

^ Mean B = includes only animals bearing viable young at termination

 

Table 4       Group mean incidence of major malformations and minor anomalies

 

Dose

(mg/kg/day)

Number of young

Incidence of pups with extra lumbar ribs

(mean %) ^

Major malformations

Minor anomalies^

Examined

Affected

Gross or visceral

Skeletal

Total number

Mean %

Examined

Affected

Examined

Affected

Total number

Mean %

Total number

Mean %

0

73

0

0

73

5

6.3

73

2

2.2

33.6

0.2

85

0

0

85

0

0

85

13

13.1

46.9

2.0

90

1

1.1

89

7

8.6

89

20

22.9

79.6*

300

85

0

0

85

3

4.2

85

8

9.4

63.5

600

16

0

0

16

1

5.6

16

2

14.3

85.7

^ young showing major malformations excluded

* Wilcoxon test (p < 0.05)

 

Conclusions:
The lowest NOAEL that could be determined for maternal toxicity was 300 mg/kg/day based on adverse clinical signs and mortality observed in the 600 mg/kg/day group.
 
The NOAEL for developmental toxicity could not be established due to the absence of adverse toxic effects at the highest concentration i.e. > 600 mg/kg/day.

This result is appropriate under a read-across approach for applicability to the target substance sodium octane-1-sulphonate monohydrate.
Executive summary:

Alcohol sulphate was examined for potential teratogenic and embryotoxic activity in rabbits. The test item was administered by oral gavage during days 6-18 pregnancy. Dosages employed were 0.2, 2.0, 300 and 600 mg/kg/day with each group consisting of 13 female individuals (New Zealand White).

 

Maternal toxicity was observed in animals treated at 600 mg/kg/day and was generally with a principle disturbance of the gastrointestinal tract, resulting in diarrhoea, anorexia, weight loss and cachexia prior to death.At the maternally toxic dose of 600 mg/kg/day, there was an increase in foetal loss and reduced litter size, due almost entirely to total litter losses. These factors were deemed to be a secondary consequence of the maternal reaction to the test item, indicated by the fact that among the rabbits bearing young at termination litter parameters were comparable to the control group

 

The incidence of major, minor, visceral and skeletal abnormalities was unaffected in rabbit pups. A statistically significant increase in the number of pups with extra ribs was observed in the 300 mg/kg/day test group. The degree of incidence was within the normal historical laboratory range, so this effect was deemed to be non-significant.

 

The lowest NOAEL that could be determined for maternal toxicity was 300 mg/kg/daybased on adverse clinical signs and mortality observed in the 600 mg/kg/day group.

 

The NOAEL for developmental toxicity could not be established due to the absence of adverse toxic effects at the highest concentration i.e. > 600 mg/kg/day.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH - See document attached in Section 13.2 for analogue read-across justification.
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
mortality
Key result
Abnormalities:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
> 600 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
The lowest NOAEL that could be determined for maternal toxicity was 300 mg/kg/day based on retarded weight gain and mortality observed in the 600 mg/kg/day group.
 
The NOAEL for developmental toxicity could not be established due to the absence of adverse toxic effects at the highest concentration i.e. > 600 mg/kg/day.

The target result corresponds to the source result from a study on a structural analogue.
Executive summary:

See document attached in Section 13.2 for analogue read-across justification.

Alcohol sulphate was examined for potential teratogenic and embryotoxic activity in rats.  The test item was administered by oral gavage during days 6-15 pregnancy.  Dosages employed were 0.2, 2.0, 300 and 600 mg/kg/day with each group consisting of 20 female individuals (CRL:CD).

 

Mild maternal toxicity was observed in animals treated at 600 mg/kg/day and was generally with a principle disturbance of the gastrointestinal tract, resulting in retarded weight gain. Rats showed no treatment-related total litter losses. Values for litter size and foetal loss were unaffected even at dosages providing evidence of maternal toxicity (600 mg/kg/day).

 

The incidence of major, minor, visceral and skeletal abnormalities was unaffected in rat pups.  A statistically significant reduction in the number of pups with extra ribs was observed in the 600 mg/kg/day test group.  The significance of this value was largely attributable to a relatively high incidence of extra-ribbed pups among the control group.  The number of pups with additional ribs for all test groups was within the expected normal laboratory range.

 

The lowest NOAEL that could be determined for maternal toxicity was 300 mg/kg/day based on retarded weight gain and mortality observed in the 600 mg/kg/day group.

 

The NOAEL for developmental toxicity could not be established due to the absence of adverse toxic effects at the highest concentration i.e. > 600 mg/kg/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subchronic
Species:
rabbit
Quality of whole database:
A reliable study consistent with information requirements at the registered tonnage band is utilised to fulfill this endpoint requirement.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Sodium dodecyl sulphate (read-across source substance) was examined for potential teratogenic and embryotoxic activity in rabbits. The test item was administered by oral gavage during days 6-18 pregnancy. Dosages employed were 0.2, 2.0, 300 and 600 mg/kg/day with each group consisting of 13 female individuals (New Zealand White).

 

Maternal toxicity was observed in animals treated at 600 mg/kg/day and was generally with a principle disturbance of the gastrointestinal tract, resulting in diarrhoea, anorexia, weight loss and cachexia prior to death. At the maternally toxic dose of 600 mg/kg/day, there was an increase in foetal loss and reduced litter size, due almost entirely to total litter losses. These factors were deemed to be a secondary consequence of the maternal reaction to the test item, indicated by the fact that among the rabbits bearing young at termination litter parameters were comparable to the control group

 

The incidence of major, minor, visceral and skeletal abnormalities was unaffected in rabbit pups. A statistically significant increase in the number of pups with extra ribs was observed in the 300 mg/kg/day test group. The degree of incidence was within the normal historical laboratory range, so this effect was deemed to be non-significant.

The lowest NOAEL that could be determined for maternal toxicity was 300 mg/kg/daybased on adverse clinical signs and mortality observed in the 600 mg/kg/day group.

The NOAEL for developmental toxicity could not be established due to the absence of adverse toxic effects at the highest concentration i.e. > 600 mg/kg/day.

Mode of Action Analysis / Human Relevance Framework

Not applicable, no reproductive or developmental effects observed in the available study.

Justification for classification or non-classification

The substance does not meet the criteria for classification in accordance with Regulation (EC) No 1272/2008 (CLP).

Additional information