Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

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

The possibility of a read-across to other alkyl sulfates in accordance with Regulation (EC) No 1907/2006 Annex XI 1.5. Grouping of substances and read-across approach was assessed. In Annex XI 1.5 it is given that a read-across approach is possible for substances, whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. The AS reported within the AS category show structural similarity. The most important common structural feature of the category members is the presence of a predominantly linear aliphatic hydrocarbon chain with a polar sulfate group, neutralized with a counter ion. This structural feature confers the surfactant properties of the alkyl sulfates. The surfactant property of the members of the AS category in turn represent the predominant attribute in mediating effects on mammalian health. Therefore, the AS of the AS category have similar physico-chemical, environmental and toxicological properties, validating the read across approach within the category. The approach of grouping different AS for the evaluation of their effects on human health and the environment was also made by the OECD in the SIDS initial assessment profile [1] and by a voluntary industry programme carrying out Human and Environmental Risk Assessments (HERA [2]), further supporting the read across approach between structurally related AS.

There is no 2-generation toxicity study with alkyl sulfates available. Nevertheless, this endpoint is sufficiently covered as data on the reproductive organs after subchronic treatment are available. Subchronic repeated oral toxicity studies with C12-15AS Na (CAS 68890-70-0), C16-18AS Na (CAS 68955-20-4) and C13-15AS Na (CAS 86014-79-1) gave no indication of adverse effects on reproductive organs (Munday et al., 1976, 1977a, 1977b). At very high doses (around or above 1000 mg/kg bw/day) increases in relative (but not absolute) testes weights were noted. This effect was not considered as adverse but was attributed to a decreased body fat/body weight ratio. There were also no adverse histopathological findings at necropsy. The primary effect after application via gavage but not after application via the diet was gastrointestinal irritation, particularly of the forestomach. Moreover it was impossible to differentiate between systemic effects as a consequence of the local irritation or due to specific substance properties. After dietary application the liver was the only target organ identified. Adaptive effects on this organ included an increase in liver weight, enlargement of liver cells and elevated levels of liver enzymes. Liver effects were more apparent in dietary studies, partly because these allowed administration of higher doses of the test material with less GI tract injury (cf. chapter on repeated dose toxicity for details on study conduct and results).

As confirmed by literature (Mangelsdorf et al. 2003, Ulbrich and Palmer 1995, Janer et al. 2007, Dent 2007, Sanbuissho et al. 2009) histopathological examinations of reproductive tissues in repeated dose toxicity studies on rodents are of high value and high sensitivity for evaluation of reproductive toxicity in males and females. Moreover, histopathological changes on the reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. Since histological examinations of the reproductive organs are covered in the studies described above, these repeated dose toxicity studies should be considered as sensitive and sufficient enough to evaluate toxicity on fertility. With additional respect to animal welfare, conducting of a two-generation reproductive toxicity study appears scientifically not of high priority. This assumption is further supported by the results of a study during which whole body radiography on rats after i.p. injection of 35S-C10AS K, C12 AS K and C18 AS K was performed. The aim was to follow the distribution of the labeled alkyl sulfates and/or their metabolites within the body with time. For all compounds the only organs, where radioactivity was detected, were the liver and the kidney. The levels (not quantified) were highest 1 h after application (cf. chapter on toxicokinetics for details). Thus, within this study the alkyl sulfates did not reach the reproductive organs. This could explain why the only relevant effects after dietary application in the repeated dose toxicity studies were observed in the liver and why no treatment related effects on the reproductive organs were observed.

Summary of in vivo data

Within the repeated dose studies no histopathological findings on reproductive organs were observed. In addition it is questionable if alkyl sulfates reach the reproductive organs. Therefore, no effects on fertility are expected and conducting a 2-generation study is not needed.

 

Further considerations

A reproductive toxicity study on a structurally similar surfactant material, alpha olefin sulfonate (AOS) was conducted. The 2-generation reproductive study (Lion Co., 1980: AOS-Mg: Effects upon the reproductive performance of rats treated continuously throughout two successive generations; unpublished report no. 80/LIF044/508) on the alpha olefin sulfonate mixture showed a complete absence of treatment-related effects on reproductive capacity or systemic organ pathology at systemic doses ranging from approximately 250-1000 mg/kg bw/day based on food intake, similar to the NOAELs in repeated dose studies on AS. The lack of reproductive organ toxicity in dietary, repeated dose studies on various AS surfactants, even at doses in excess of the NOAELs, provides further corroboration for the absence of specific, surfactant-mediated effects on the reproductive organs. The comparable toxicokinetic and metabolic profiles, as well as their toxicological similarities for this and other toxicological endpoints, support the conclusion that insights from the reproductive toxicity study on AOS are applicable to AS.

With regard to animal welfare this read across should be considered to close the data gap in case that waiving of this endpoint seems not sufficient. A more detailed rationale for a read across from AOS to AS would be handed in subsequently.

REFERENCES

[1] SIDS initial assessment profile, (2007);
http://www.aciscience.org/docs/Alkyl_Sulfates_Final_SIAP.pdf

[2] (HERA Draft report, 2002);
http://www.heraproject.com/files/3-HH-04-%20HERA%20AS%20HH%20web%20wd.pdf


Effects on developmental toxicity

Description of key information
OECD 414, rat, developmental toxicity, oral: not teratogenic
Maternal: NOEL = 250 mg/kg bw/day; LOEL > 250 mg/kg bw/day
Developmental: NOEL = 250 mg/kg bw/day; LOEL > 250 mg/kg bw/day
Link to relevant study records

Referenceopen allclose all

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:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
According to Guideline.
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Concentration in vehicle: 10%
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
According to Guideline.
Duration of treatment / exposure:
Day 6-15 of gestation.
Frequency of treatment:
Once daily.
Duration of test:
Day 21 and Post parturition, resp.
No. of animals per sex per dose:
20 females (15 for dissection; 5 for natural parturition)
Control animals:
yes, concurrent vehicle
Maternal examinations:
Acording to Guideline, except for parturition. Except of killing one day prior to the expected day of delivery, five of 20 dams were allotted to natural parturition before sacrifice.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: YesExaminations 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: Five mated rats from each of the treatment and ten from the control group were selected by random numbers for natural parturition. This enabled observations on litter size, weight and infant mortality to be recorded, together with any other observable postpartum expression of response to treatment for a period of 21 days (birth to weaning).
Fetal examinations:
- External examinations: Yes- Soft tissue examinations: Yes- Skeletal examinations: Yes- Head examinations: No
Statistics:
Yes
Details on maternal toxic effects:
Maternal toxic effects:yesDetails on maternal toxic effects:At 500 mg/kg bw/day, the test substance produced maternal toxicity associated with severe diarrhoea, reduced food intake and reduced body weight gain. There was one death in this group and two animals were killed prior to full term. The survivors showed an increased number of intrauterine deaths and a reduction in live foetal body weight. These foetuses showed evidence of toxic retardation, with delayed ossification and also an increased incidence of supernumerary cervical ribs and shortened thoracic ribs. There were no gross external or visceral anomalies which could be attributed to treatment. No maternal toxic effects were seen in the other treatment groups and there were no effects on live foetal numbers, body weight or crown-rump distance. There was no evidence of a specific external, gross viscera1 or skeletal defect which could be attributed to treatment. There was no indication of a treatment effect on pups born by natural parturition and reared to weaning age of 21 days.
Dose descriptor:
NOEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: No toxic effects.
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effectsDetails on embryotoxic / teratogenic effects:Effects were only seen in the presence of maternal toxicity.85586-07-8
Dose descriptor:
NOEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: No toxic effects.
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
Treatment of pregnant rats with Alfol 12-14 sulphate at 500 mg/kg bw/day induced a maternal toxic response and this was reflected in the conception which showed toxic retardation. At 250, 125 and 63 mg/kg bw/day, Alfol 12-14 sulphate did not cause maternal toxicity or foetotoxicity and did not show teratogenic potential.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
According to guideline.
Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
According to guideline.
Duration of treatment / exposure:
Day 6-18
Frequency of treatment:
Daily
Duration of test:
Day 1-29
No. of animals per sex per dose:
13
Control animals:
yes, concurrent vehicle
Maternal examinations:
According to guideline.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: YesExaminations included:- Gravid uterus weight: No- Number of corpora lutea: Yes- Number of implantations: Yes- Number of early resorptions: Yes- Number of late resorptions: Yes
Fetal examinations:
- External examinations: No data- Soft tissue examinations: Yes- Skeletal examinations: Yes- Head examinations: No
Statistics:
Yes.
Details on maternal toxic effects:
Maternal toxic effects:yes
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
600 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Dose descriptor:
NOAEL
Effect level:
> 600 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
No maternal toxicity and no developmental toxicity up to 300 and 600 mg/kg/day, respectively.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
rat
Strain:
other: CD
Details on test animals and environmental conditions:
According to guideline.
Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
According to guideline.
Duration of treatment / exposure:
Day 6-15 p.c.
Frequency of treatment:
Daily
Duration of test:
Day 20
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Maternal examinations:
According to guideline.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: YesExaminations included:- Gravid uterus weight: No- Number of corpora lutea: Yes- Number of implantations: Yes- Number of early resorptions: Yes- Number of late resorptions: Yes
Fetal examinations:
- External examinations: No data- Soft tissue examinations: Yes- Skeletal examinations: Yes- Head examinations: No
Statistics:
Yes.
Details on maternal toxic effects:
Maternal toxic effects:yes
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
600 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Dose descriptor:
NOAEL
Effect level:
> 600 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
At 600 mg/kg bw no developmental toxicity was detected. Maternal toxicity was present at 600 mg/kg bw.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
Age: 16 - 18 weeks
Route of administration:
oral: gavage
Details on mating procedure:
Virgin female rats were taken at random from a stock  cage and recaged in groups of 3 with each of 15 virgin male rats of the  same age and from the same colony. The dropping trays were examined each  morning thereafter for ejected vaginal plugs, and when these were found  the female rats were removed and individually examined for evidence of  mating. Confirmation of mating was established by microscopically  examination of the vaginal mucus for the presence of spermatozoa.
Duration of treatment / exposure:
Days 6 - 15 of gestation
Frequency of treatment:
daily
Duration of test:
Termination on Day 21 of gestation or up to weaning Day 21.
No. of animals per sex per dose:
15 rats (10 for dissection, 5 for  natural parturition)
Control animals:
yes
Details on study design:
negative control: saline positive control: aspirin 250 mg/kg  s.c.
Maternal examinations:
-body weight: daily -maternal food intake: daily
Ovaries and uterine content:
- mean gravid uterus weight & mean weight of uterine tissue- intrauterine mortality - mean response per pregnancy
Fetal examinations:
- mean foetal body weight, crown  rump distance and mean placental weight-  % incidence of external and  gross visceral observations of foetuses- incidence of skeletal  variants/anomalies of foetuses- incidence and distribution of other  anomalies- post-partum mortalities- mean body weight of pups (at birth  and on days 7, 14 and 21)- weaned of born- incidence of external and  gross visceral variations of pups- incidence of skeletal variations of  pups
Details on maternal toxic effects:
Maternal toxic effects:yesDetails on maternal toxic effects:General health: All animals at 500 mg/kg had diarrhoea, which continued until cessation  of treatment. With successive treatments the passage of the cannula down  the oesophagus became more difficult suggesting a dryness of the  membranes, and the demeanour of the animals became more aggressive.  Between the 4th and 8th dose 4 of the animals of this group died and 1  was killed because of its condition. A further animal aborted on the 14th  day of gestation having received 9 treatments. All the animals which died  showed evidence of gastrointestinal irritation and diffuse haemorrhage of  the stomach. In 3 instances there was also congestion of the lungs. Mean maternal body weight gain: Treatment with 500 mg/kg induced a significant (p = < 0.05) reduction in  maternal body weight gain during the period of treatment. Food consumption: Rats treated with 500 mg/kg consumed significantly (p=<0.05) less food  than controls Intrauterine mortality: No significant differences between treatment and control Mean response per pregnancy: Treatment did not adversely affect the pre- or post-implantation loss
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effectsDetails on embryotoxic / teratogenic effects:Foetal and placental size: The mean placental weight for male and female foetuses combined and  considered separately were significantly lower in animals fed 500 mg/kg  (p= 0.05). Incidence of gross variants/anomalies: No significant differences between treatment groups and control group Incidence of skeletal anomalies: No significant differences between treatment groups and control group Incidence of foetal variations, minor anomalies and major malformations: Malformations were found in 3 foetuses from dams treated with 500 mg/kg -  protruding tongue, gross oedema and shortening of the pubic bone;  agenesis of eyelids and cleft palate; unossified metatarsus and claw in  left hind foot. The foetuses were all taken from separate pregnancies. A  single live foetus with a malformation was also found after treatment  with 250 mg/kg (hermi-centric lumbar centra with asymmetry and reduced  ossification of the 6th lumbar arch and scoliosis) and 63 mg/kg  (unossified and dumbbell shaped thoracic centrae associated with branched  ribs) Rats allocated to natural parturition: Post-partum mortalities: No significant differences between treatment and controls. Incidence of skeletal defects in rat pups: No significant differences between treatment groups and control group.
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
rat
Strain:
Wistar
Route of administration:
oral: gavage
Duration of treatment / exposure:
Day 6 - 15 of gestation
Frequency of treatment:
daily
Duration of test:
termination on GD 21 or up to weaning day 21
No. of animals per sex per dose:
15 females per dose group: 10 for dissection and 5  for natural parturition
Control animals:
yes, concurrent vehicle
Dose descriptor:
NOAEL
Effect level:
225 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
450 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
675 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: embryotoxicity
Dose descriptor:
LOAEL
Effect level:
> 675 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: embryotoxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Maternal effects:
General health: Treatment with 675 mg/kg induced diarrhoea in 4/15 females

after the third dose day (day 9 of gestation)
Mean maternal body weight gain: the mean maternal body weight gain in rats 

fed 675 mg/kg on days 6-10 and rats fed 450 mg/kg on days 10-15 of gestation 

were significantly lower (p = < 0.05) than controls
Food consumption: no significant differences between treatment and control groups
Intrauterine mortality: no significant differences between treatment and control
Mean response per pregnancy: When data for live foetuses was analysed there

was significantly less (p=<0.05) live foetuses in the 675 mg/kg group 

than the controls. This was not attributable, however, to a significant 

decrease in viable female foetuses in this group, but purely a chance 

occurrence of a high number of female foetuses in the controls.

Offspring:
Foetal and placental size: Only significant effect when data for the 

separate males and females was analysed which revealed a significantly 

lower (p= <0.05) mean placental weight for the male foetuses in the 450 

mg/kg group
Incidence of gross variants/anomalies: No explanation could be given for 

the incidence of macroscopically observed haemorrhage under the capsule 

of the kidney in some foetuses in the 3 lower treatment groups (3.66% of 

foetuses at 450 mg/kg; 3.73% at 225 mg/kg; 4.95% at 112 mg/kg).
Incidence of skeletal anomalies: Analysis of the data relating to 

vertebral and head variations/anomalies revealed a significant (p=<0.05) 

increase in the foetuses from mothers treated with 112 mg/kg

Rats allocated to natural parturition
Post-partum mortalities: In the 675 mg/kg body weight treatment group 5/6 

pups were partially cannibalised during post-partum days 1-3 and all came 

from a single litter. Two pups from a single litter were also cannibalised 

in the 450 mg/kg body weight treatment group.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Partially natural parturition.
GLP compliance:
no
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
According to Guideline.
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Concentration in vehicle: 10%
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
According to Guideline.
Duration of treatment / exposure:
Day 6-15 of gestation.
Frequency of treatment:
Once daily.
Duration of test:
Day 21 and Post parturition, resp.
No. of animals per sex per dose:
20 females (15 for dissection; 5 for natural parturition)
Control animals:
yes, concurrent vehicle
Maternal examinations:
Acording to Guideline, except for parturition. Except of killing one day prior to the expected day of delivery, five of 20 dams were allotted to natural parturition before sacrifice.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: YesExaminations 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: Five mated rats from each of the treatment and ten from the control group were selected by random numbers for natural parturition. This enabled observations on litter size, weight and infant mortality to be recorded, together with any other observable postpartum expression of response to treatment for a period of 21 days (birth to weaning).
Fetal examinations:
- External examinations: Yes- Soft tissue examinations: Yes- Skeletal examinations: Yes- Head examinations: No
Statistics:
Yes
Details on maternal toxic effects:
Maternal toxic effects:yesDetails on maternal toxic effects:At 500 mg/kg bw/day, the test substance produced maternal toxicity associated with severe diarrhoea, reduced food intake and reduced body weight gain. There was one death in this group and two animals were killed prior to full term. The survivors showed an increased number of intrauterine deaths and a reduction in live foetal body weight. These foetuses showed evidence of toxic retardation, with delayed ossification and also an increased incidence of supernumerary cervical ribs and shortened thoracic ribs. There were no gross external or visceral anomalies which could be attributed to treatment. No maternal toxic effects were seen in the other treatment groups and there were no effects on live foetal numbers, body weight or crown-rump distance. There was no evidence of a specific external, gross viscera1 or skeletal defect which could be attributed to treatment. There was no indication of a treatment effect on pups born by natural parturition and reared to weaning age of 21 days.
Dose descriptor:
NOEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: No toxic effects.
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effectsDetails on embryotoxic / teratogenic effects:Effects were only seen in the presence of maternal toxicity.85586-07-8
Dose descriptor:
NOEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: No toxic effects.
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
Treatment of pregnant rats with Alfol 12-14 sulphate at 500 mg/kg bw/day induced a maternal toxic response and this was reflected in the conception which showed toxic retardation. At 250, 125 and 63 mg/kg bw/day, Alfol 12-14 sulphate did not cause maternal toxicity or foetotoxicity and did not show teratogenic potential.
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
lack of details on test substance, intervals in dose range
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
According to guideline.
Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
According to guideline.
Duration of treatment / exposure:
Day 6-18
Frequency of treatment:
Daily
Duration of test:
Day 1-29
No. of animals per sex per dose:
13
Control animals:
yes, concurrent vehicle
Maternal examinations:
According to guideline.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: YesExaminations included:- Gravid uterus weight: No- Number of corpora lutea: Yes- Number of implantations: Yes- Number of early resorptions: Yes- Number of late resorptions: Yes
Fetal examinations:
- External examinations: No data- Soft tissue examinations: Yes- Skeletal examinations: Yes- Head examinations: No
Statistics:
Yes.
Details on maternal toxic effects:
Maternal toxic effects:yes
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
600 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Dose descriptor:
NOAEL
Effect level:
> 600 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
No maternal toxicity and no developmental toxicity up to 300 and 600 mg/kg/day, respectively.
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Lack of details on test substance, intervals in dose range
GLP compliance:
no
Species:
rat
Strain:
other: CD
Details on test animals and environmental conditions:
According to guideline.
Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
According to guideline.
Duration of treatment / exposure:
Day 6-15 p.c.
Frequency of treatment:
Daily
Duration of test:
Day 20
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Maternal examinations:
According to guideline.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: YesExaminations included:- Gravid uterus weight: No- Number of corpora lutea: Yes- Number of implantations: Yes- Number of early resorptions: Yes- Number of late resorptions: Yes
Fetal examinations:
- External examinations: No data- Soft tissue examinations: Yes- Skeletal examinations: Yes- Head examinations: No
Statistics:
Yes.
Details on maternal toxic effects:
Maternal toxic effects:yes
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
600 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Dose descriptor:
NOAEL
Effect level:
> 600 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
At 600 mg/kg bw no developmental toxicity was detected. Maternal toxicity was present at 600 mg/kg bw.
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment Adopted according to OECD SIDS or other official EU regulation procedures (public available peer reviewed source).
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Principles of method if other than guideline:
Method: other
GLP compliance:
no
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
Age: 16 - 18 weeks
Route of administration:
oral: gavage
Details on mating procedure:
Virgin female rats were taken at random from a stock  cage and recaged in groups of 3 with each of 15 virgin male rats of the  same age and from the same colony. The dropping trays were examined each  morning thereafter for ejected vaginal plugs, and when these were found  the female rats were removed and individually examined for evidence of  mating. Confirmation of mating was established by microscopically  examination of the vaginal mucus for the presence of spermatozoa.
Duration of treatment / exposure:
Days 6 - 15 of gestation
Frequency of treatment:
daily
Duration of test:
Termination on Day 21 of gestation or up to weaning Day 21.
No. of animals per sex per dose:
15 rats (10 for dissection, 5 for  natural parturition)
Control animals:
yes
Details on study design:
negative control: saline positive control: aspirin 250 mg/kg  s.c.
Maternal examinations:
-body weight: daily -maternal food intake: daily
Ovaries and uterine content:
- mean gravid uterus weight & mean weight of uterine tissue- intrauterine mortality - mean response per pregnancy
Fetal examinations:
- mean foetal body weight, crown  rump distance and mean placental weight-  % incidence of external and  gross visceral observations of foetuses- incidence of skeletal  variants/anomalies of foetuses- incidence and distribution of other  anomalies- post-partum mortalities- mean body weight of pups (at birth  and on days 7, 14 and 21)- weaned of born- incidence of external and  gross visceral variations of pups- incidence of skeletal variations of  pups
Details on maternal toxic effects:
Maternal toxic effects:yesDetails on maternal toxic effects:General health: All animals at 500 mg/kg had diarrhoea, which continued until cessation  of treatment. With successive treatments the passage of the cannula down  the oesophagus became more difficult suggesting a dryness of the  membranes, and the demeanour of the animals became more aggressive.  Between the 4th and 8th dose 4 of the animals of this group died and 1  was killed because of its condition. A further animal aborted on the 14th  day of gestation having received 9 treatments. All the animals which died  showed evidence of gastrointestinal irritation and diffuse haemorrhage of  the stomach. In 3 instances there was also congestion of the lungs. Mean maternal body weight gain: Treatment with 500 mg/kg induced a significant (p = < 0.05) reduction in  maternal body weight gain during the period of treatment. Food consumption: Rats treated with 500 mg/kg consumed significantly (p=<0.05) less food  than controls Intrauterine mortality: No significant differences between treatment and control Mean response per pregnancy: Treatment did not adversely affect the pre- or post-implantation loss
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effectsDetails on embryotoxic / teratogenic effects:Foetal and placental size: The mean placental weight for male and female foetuses combined and  considered separately were significantly lower in animals fed 500 mg/kg  (p= 0.05). Incidence of gross variants/anomalies: No significant differences between treatment groups and control group Incidence of skeletal anomalies: No significant differences between treatment groups and control group Incidence of foetal variations, minor anomalies and major malformations: Malformations were found in 3 foetuses from dams treated with 500 mg/kg -  protruding tongue, gross oedema and shortening of the pubic bone;  agenesis of eyelids and cleft palate; unossified metatarsus and claw in  left hind foot. The foetuses were all taken from separate pregnancies. A  single live foetus with a malformation was also found after treatment  with 250 mg/kg (hermi-centric lumbar centra with asymmetry and reduced  ossification of the 6th lumbar arch and scoliosis) and 63 mg/kg  (unossified and dumbbell shaped thoracic centrae associated with branched  ribs) Rats allocated to natural parturition: Post-partum mortalities: No significant differences between treatment and controls. Incidence of skeletal defects in rat pups: No significant differences between treatment groups and control group.
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Principles of method if other than guideline:
Method: other
GLP compliance:
no
Species:
rat
Strain:
Wistar
Route of administration:
oral: gavage
Duration of treatment / exposure:
Day 6 - 15 of gestation
Frequency of treatment:
daily
Duration of test:
termination on GD 21 or up to weaning day 21
No. of animals per sex per dose:
15 females per dose group: 10 for dissection and 5  for natural parturition
Control animals:
yes, concurrent vehicle
Dose descriptor:
NOAEL
Effect level:
225 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
450 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
675 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: embryotoxicity
Dose descriptor:
LOAEL
Effect level:
> 675 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: embryotoxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Maternal effects:
General health: Treatment with 675 mg/kg induced diarrhoea in 4/15 females

after the third dose day (day 9 of gestation)
Mean maternal body weight gain: the mean maternal body weight gain in rats 

fed 675 mg/kg on days 6-10 and rats fed 450 mg/kg on days 10-15 of gestation 

were significantly lower (p = < 0.05) than controls
Food consumption: no significant differences between treatment and control groups
Intrauterine mortality: no significant differences between treatment and control
Mean response per pregnancy: When data for live foetuses was analysed there

was significantly less (p=<0.05) live foetuses in the 675 mg/kg group 

than the controls. This was not attributable, however, to a significant 

decrease in viable female foetuses in this group, but purely a chance 

occurrence of a high number of female foetuses in the controls.

Offspring:
Foetal and placental size: Only significant effect when data for the 

separate males and females was analysed which revealed a significantly 

lower (p= <0.05) mean placental weight for the male foetuses in the 450 

mg/kg group
Incidence of gross variants/anomalies: No explanation could be given for 

the incidence of macroscopically observed haemorrhage under the capsule 

of the kidney in some foetuses in the 3 lower treatment groups (3.66% of 

foetuses at 450 mg/kg; 3.73% at 225 mg/kg; 4.95% at 112 mg/kg).
Incidence of skeletal anomalies: Analysis of the data relating to 

vertebral and head variations/anomalies revealed a significant (p=<0.05) 

increase in the foetuses from mothers treated with 112 mg/kg

Rats allocated to natural parturition
Post-partum mortalities: In the 675 mg/kg body weight treatment group 5/6 

pups were partially cannibalised during post-partum days 1-3 and all came 

from a single litter. Two pups from a single litter were also cannibalised 

in the 450 mg/kg body weight treatment group.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subchronic
Species:
rat
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

The possibility of a read-across to other alkyl sulfates in accordance with Regulation (EC) No 1907/2006 Annex XI 1.5. Grouping of substances and read-across approach was assessed. In Annex XI 1.5 it is given that a read-across approach is possible for substances, whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. The AS reported within the AS category show structural similarity. The most important common structural feature of the category members is the presence of a predominantly linear aliphatic hydrocarbon chain with a polar sulfate group, neutralized with a counter ion. This structural feature confers the surfactant properties of the alkyl sulfates. The surfactant property of the members of the AS category in turn represent the predominant attribute in mediating effects on mammalian health. Therefore, the AS of the AS category have similar physico-chemical, environmental and toxicological properties, validating the read across approach within the category. The approach of grouping different AS for the evaluation of their effects on human health and the environment was also made by the OECD in the SIDS initial assessment profile [1] and by a voluntary industry programme carrying out Human and Environmental Risk Assessments (HERA [2]), further supporting the read across approach between structurally related AS.

In the developmental toxicity study which was chosen as key study C12-14AS Na (CAS 85586-07-8) was administered orally by gavage to pregnant Wistar rats at dose levels of 0, 63, 125, 250 and 500 mg/kg bw/day once daily from Day 6 to 15 of gestation (Cambridge, 1987). In summary, C12-14AS Na (CAS 85586-07-8) induced maternal toxicity, indicated by body weight decrease, diarrhoea and increased mortality, when administered at doses of 500 mg/kg bw/day. Developmental toxicity could be seen by an increased number of intrauterine deaths, a decreased live foetal body weight and toxic retardation with delayed ossification and increased incidence of supernumerary cervical ribs and shortened thoracic rib at 500 mg/kg bw/day. Based on the available information the NOEL for maternal toxicity and developmental toxicity is set at 250 mg/kg bw/day.

The purpose of the study conducted by Palmer (1975) was to assess the effects of orally administered C12AS Na (CAS 151-21-3) on embryonic and foetal development in pregnant CD-rats and NZW-rabbits. In this study, C12AS Na (CAS 151-21-3) was administered orally by gavage at dose levels of 0, 0.2, 2, 300 and 600 mg/kg bw/day once daily from Day 6 to Day 15 (rat) / Day 19 (rabbit) of gestation. In summary, the results of the study showed that repeated oral administration of C12AS Na (CAS 151-21-3) to pregnant rats and rabbits did not cause symptoms of cumulative maternal toxicity up to a dose level of 300 mg/kg bw/day. There were no treatment-related foetal abnormalities at necropsy and no treatment-related effects in the reproduction data. Thus, based on the available information, the NOAEL for teratogenicity and developmental toxicity are assessed to be greater than 600 mg/kg bw/day.

The effect of C12AS Na (CAS 151-21-3) on embryonic and foetal development was as well assessed by Unilever (1976) in Wistar rats. The test substance was administered by gavage at dose levels of 0, 63, 125, 250 and 500 mg/kg bw/day once daily from Day 6 to 15 of gestation. No cumulative maternal toxicity was seen up to a dose level of 250 mg/kg bw/day. At 500 mg/kg bw/day dams showed significant decreased body weight and food consumption together with corresponding clinical signs like diarrhoea. No treatment-related foetal abnormalities or effects in the reproduction data were observed at 500 mg/kg bw/day. Thus, the NOAEL for teratogenicity and developmental toxicity are assessed to be greater than 500 mg/kg bw/day.

Finally, embryonic and foetal development was examined after administration of C16-18AS Na (CAS 68955-20-4; Unilever, 1978). The alkyl sulfate was administered by gavage at dose levels of 0, 112, 225, 450 and 675 mg/kg bw/day once daily from Day 6 to 15 of gestation. At 450 mg/kg bw/day and higher dams showed significant decreased body weight gain together with diarrhoea. No treatment-related foetal abnormalities or effects in the reproduction data were observed at 675 mg/kg bw/day. Thus, the NOAEL for teratogenicity and developmental toxicity are assessed to be greater than 675 mg/kg bw/day.

Conclusion

In the repeated dose studies it was observed that the primary effect after application via gavage is gastrointestinal irritation. This is consistent with the primary irritant properties of the AS and the bolus effect after application by gavage. Moreover, it was impossible to differentiate between systemic effects as a consequence of the local irritation or due to specific substance properties.

In the developmental toxicity study where teratogenic effects were observed, these occured at the highest dose level after oral gavage. However at this dose level signs of marked maternal toxicity, i.e. increased mortality was observed. At dose levels inducing no maternal toxicity no teratogenicity was observed.Thus, AS are not teratogenic.

REFERENCES

[1] SIDS initial assessment profile, (2007);
http://www.aciscience.org/docs/Alkyl_Sulfates_Final_SIAP.pdf

[2] (HERA Draft report, 2002);
http://www.heraproject.com/files/3-HH-04-%20HERA%20AS%20HH%20web%20wd.pdf

Justification for classification or non-classification

The available data on reproductive toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.