Sulfuric acid, mono-C12-14 (even numbered)-alkyl esters, compds. with ethanolamine

Endpoint summary

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 counterion. 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 physicochemical, 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 a substantial data base on the counter ion ethanolamine (MEA) online available. MEA is listed in Annex VI of Regulation 1272/2008. It is classified Acute Tox. 4; H302, H312 and H332 as well as Skin Corr. 1B; H314. Additionally a specific concentration limit is established for STOT SE3, H335 at concentrations ≥ 5% in Annex VI of Regulation 1272/2008. The effects of MEA on human health were assessed by the OECD in the SIDS initial assessment Report [3]. No long-term toxicity study with Monoethanolamine is available. However in a dietary two generation toxicity study with MEA the NOAEL was established at 300 mg/kg bw/d based on reduced body weight gain and food consumption at 1000 mg/kg bw/d. When this NOAEL is corrected for differences in molecular weight (61 g/mol for MEA and 340 g/mol for C12-14AS MEA) this results in a NOAEL of 1672 mg/kg bw/d for C12-14AS MEA. Thus, MEA will not confer adverse effects on fertility/reproduction of C12-14AS MEA.

Reproductive toxicity of alkyl sulfates

The endpoint reproductive toxicity is sufficiently covered by weight of evidence approach. A two-generation reproductive toxicity study is deemed to be not required based on the following discussion.

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 a two-generation reproductive toxicity study appears scientifically not of high priority. This assumption is further supported by the results of a study in which whole body radiography on rats after i.p. injection of 35S-C10AS K, C12 AS K and C18 AS K was performed (cf. chapter on toxicokinetics for details). 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 liver and kidneys. The levels (not quantified) were highest 1 h after application. 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

However, 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

[3] SIDS initial assessment report, (2013);

http://webnet.oecd.org/HPV/UI/SIDS_Details.aspx?key=8aefe41b-8499-4052-943f-f6dd6f8c5997&idx=0

 

Short description of key information:
Waived

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

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to Guideline study with acceptable restrictions.

Qualifier:

equivalent or similar to guideline

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 or test system 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.

Remarks:

Doses / Concentrations:
0, 63, 125, 250, 500 mg/kg
Basis:
nominal conc.

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: Yes

Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

- Other: 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:yes

Details 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 effects

Details on embryotoxic / teratogenic effects:
Effects were only seen in the presence of maternal toxicity.85586-07-8

Dose descriptor:

NOEC

Effect level:

250 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no toxic effects

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.

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 counterion. 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 physicochemical, 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 a substantial data base on the counter ion ethanolamine (MEA) online available. MEA is listed in Annex VI of Regulation 1272/2008. It is classified Acute Tox. 4; H302, H312 and H332 as well as skin corr. 1B; H314. Additionally a specific concentration limit is established for STOT SE3, H335 at concentrations ≥ 5% in Annex VI of Regulation 1272/2008. The effects of MEA on human health were assessed by the OECD in the SIDS initial assessment Report [3]. In several OECD Guideline studies no developmental toxicity at non-maternal toxic doses was reported. Thus, MEA will not confer adverse effects on developing pups.

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 was 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

[3] SIDS initial assessment report, (2013);

http://webnet.oecd.org/HPV/UI/SIDS_Details.aspx?key=8aefe41b-8499-4052-943f-f6dd6f8c5997&idx=0

Justification for selection of Effect on developmental toxicity: via oral route:
The study from which the NOAEL was chosen was selected.

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.