Sodium 2-hydroxyethanesulphonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The performance of an Extended one-generation reproductive toxicity study (OECD TG 443) was waived following two adaptations: (1) Annex XI section 3.2(a) “Substance-tailored exposure-driven testing” and (2) a Next Generation Safety Assessment (NGSA) using New Approach Methodologies (NAMs) applied in accordance with Annex XI section 1.2 “weight of evidence”. 

The approaches are explained in detail in the narrative document attached in section 13.

In short, a comprehensive exposure assessment was conducted covering all potential routes of human exposure during manufacture and use of sodium 2-hydroxyethansulphonate (SI). DNELs have been calculated using standard assessment factors as laid out in REACH guidance documents based on legacy animal data for SI, specifically the study reporting the most sensitive (lowest) and hence most conservative no observed adverse effect level (NOAEL); i.e., a 90-day oral subchronic study which reported the NOAEL as 200 mg/kg bw/day. An additional assessment factor of two was applied during the DNEL calculation to account for the increased uncertainty resulting from the omission of the information requirement. The calculated RCRs (Risk Characterisation Ratio's) for each registrant were all well below 0.5 confirming that the risks of SI are controlled throughout its life cycle. 

It was taking into account that there are no effects in the reproductive tissues seen in the existing, reliable studies. No substance related gross pathological or histological changes were reported in the gonads and associated sexual tissues. There were no observations in the 90 day study that would indicate a concern for fertility. No maternal or developmental effects were observed up to 1000 mg/kg bw/d in the OECD 414 study conducted in rats.

In addition, there is sufficient weight of evidence from the use of newly developed test methods, i.e., a Next Generation Safety Assessment (“NGSA”) to conclude that no bioactivity is expected during/following the registered uses of SI. This demonstrates that SI does not have the reproductive toxicity properties sought to be addressed by the requested testing.

Taking into account the considerations above the registrants conclude that the conduct of additional vertebrate animal tests with SI is not justified and would run contrary to Article 25 REACH according to which animal testing should be performed only as the last resort (Article 25 REACH).

 

Link to relevant study records

Reference

Reference 1

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

other justification

Justification for data waiving:

other:

Justification for type of information:

A Next Generation Safety Assessment (NGSA) was performed, which is an exposure-led approach to safety assessment that employs the use of multiple New Approach Methodologies (NAMs). This NGSA demonstrates that no bioactivity is expected during/following registered uses of SI, hence allowing to conclude that SI does not have the reproductive toxicity properties and that there can be no adverse effects. This is further described in the narrative document attached in section 13, including the Registrants’ joint Response to ECHA Compliance Check Decision of 27 May 2020.

Reason / purpose for cross-reference:

data waiving: supporting information

Reference 2

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

other justification

Justification for data waiving:

the study does not need to be conducted because relevant human exposure can be excluded as demonstrated in the relevant exposure assessment

Justification for type of information:

A rigorous exposure assessment was performed covering the entire life cycle of SI. The most conservative DNEL relevant and appropriate for the endpoint was derived from the existing in vivo 90-day study. The calculated RCRs (Risk Characterization Ratio's) demonstrate that exposures are always well below the derived DNEL and confirm that the risks of SI are controlled throughout its life cycle. Therefore, it is concluded that there is no significant exposure to humans. According to section 3.1 and section 3.2(a) of Annex XI, the testing for this endpoint is omitted. This is further described in the narrative documents attached in section 13, including the Registrants’ joint Response to ECHA Compliance Check Decision of 27 May 2020.

Reason / purpose for cross-reference:

assessment report

Reproductive effects observed:

not specified

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

Effects on developmental toxicity

Description of key information

The performance of a developmental toxicity study (OECD TG 414) in a second species was waived following two adaptations: (1) Annex XI section 3.2(a) “Substance-tailored exposure-driven testing” and (2) a Next Generation Safety Assessment (NGSA) using New Approach Methodologies (NAMs) applied in accordance with Annex XI section 1.2 “weight of evidence”. 

The approaches are explained in detail in the narrative document attached in section 13.

In short, a comprehensive exposure assessment was conducted covering all potential routes of human exposure during manufacture and use of sodium 2-hydroxyethansulponate (SI). DNELs have been calculated using standard assessment factors as laid out in REACH guidance documents based on legacy animal data for SI, specifically the study reporting the most sensitive (lowest) and hence most conservative no observed adverse effect level (NOAEL); i.e., a 90-day oral subchronic study which reported the NOAEL as 200 mg/kg bw/day. An additional assessment factor of two was applied during the DNEL calculation to account for the increased uncertainty resulting from the omission of the information requirement. The calculated RCRs (Risk Characterisation Ratios) for each registrant were all well below 0.5 confirming that the risks of SI are controlled throughout its life cycle. 

It was taking into account that the developmental properties of SI were studied in a developmental toxicity study in rats (OECD TG 414, Klimisch 1 study). Four groups of females were dosed with 0, 50, 200 and 1000 mg/kg bw/d from day 0 to day 20 post coitum. All females were sacrificed on day 21 post coitum and the fetuses were removed by Caesarean section. All dams survived. No maternal or developmental effects were observed up to 1000 mg/kg bw/d.

In addition, there is sufficient weight of evidence from the use of newly developed test methods, i.e., a Next Generation Safety Assessment (“NGSA”) to conclude that no bioactivity is expected during/following the registered uses of SI. The assays used in this approach included developmental and reproductive toxicity (DART) related in vitro assays, in which no bioactivity of SI was observed (included in section 7.9). This demonstrates that SI does not have the reproductive toxicity properties sought to be addressed by the requested testing.

Taking into account the considerations above the registrants conclude that the conduct of additional vertebrate animal tests with SI is not justified and would run contrary to Article 25 REACH according to which animal testing should be performed only as the last resort (Article 25 REACH).

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Remarks:

2nd species (rabbit)

Data waiving:

other justification

Justification for data waiving:

other:

Justification for type of information:

A Next Generation Safety Assessment (NGSA) was performed, which is an exposure-led approach to safety assessment that employs the use of multiple New Approach Methodologies (NAMs). This NGSA demonstrates that no bioactivity is expected during/following registered uses of SI, hence allowing to conclude that SI does not have the reproductive toxicity properties and that there can be no adverse effects. This is further described in the narrative document attached in section 13, including the Registrants’ joint Response to ECHA Compliance Check Decision of 27 May 2020.

Reason / purpose for cross-reference:

data waiving: supporting information

Species:

rabbit

Abnormalities:

not specified

Developmental effects observed:

not specified

Reference 2

Endpoint:

developmental toxicity

Data waiving:

exposure considerations

Justification for data waiving:

the study does not need to be conducted because relevant human exposure can be excluded as demonstrated in the relevant exposure assessment

Justification for type of information:

A rigorous exposure assessment was performed covering the entire life cycle of SI. The most conservative DNEL relevant and appropriate for the endpoint was derived from the existing in vivo 90-day study. The calculated RCRs (Risk Characterization Ratio's) demonstrate that exposures are always well below the derived DNEL and confirm that the risks of SI are controlled throughout its life cycle. Therefore, it is concluded that there is no significant exposure to humans. According to section 3.1 and section 3.2(a) of Annex XI, the testing for this endpoint is omitted. This is further described in the narrative documents attached in section 13, including the Registrants’ joint Response to ECHA Compliance Check Decision of 27 May 2020.

Reason / purpose for cross-reference:

assessment report

Species:

rabbit

Reference 3

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2008-08-19 till 2009-02-11

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline conform study under GLP without deviations

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: MAFF, 12 Nohsan No. 8147 2000-11-04

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Rat, HanRcc: WIST(SPF) Harlan Laboratories Ltd., Laboratory Animal Services, 4414 Füllinsdorf / Switzerland
- Age at study initiation: 11 weeks
- Weight at study initiation: 188 to 220 g
- Housing: females were housed with sexually mature males (1:1) in special automatic mating cages i.e. with synchronized timing to initiate the nightly mating period, until evidence of copulation was observed. The females were removed and housed individually if: a) The daily vaginal smear was sperm positive, or b) A copulation plug was observed.
- Diet (e.g. ad libitum): Pelleted standard Kliba Nafag 3433 rat/mouse maintenance diet was available ad libitum.
- Water (e.g. ad libitum): Community tap-water from Füllinsdorf , ad libitum
- Acclimation period: 7 days, under test conditions after health examination. Only animals without any visible signs of illness were used for the study


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): relative humidity range: 30 - 70%)
- Air changes (per hr): 10 - 15 air changes per hour
- Photoperiod (hrs dark / hrs light):12-hour fluorescent light / 12-hour dark cycle with music during the light period.

Route of administration:

oral: gavage

Vehicle:

other: highly purified water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:


DIET PREPARATION
The dose formulations were prepared weekly using the test item as supplied by the Sponsor.
The test item was weighed into a tared glass container on a suitable precision balance and the
vehicle was added to give the appropriate final concentration of the test item in the dose
formulation. The mixture was prepared using a magnetic stirrer or homogenizer as appropriate.
Homogeneity of the test item in the vehicle was maintained during the daily administration
period using a magnetic stirrer.

Storage of Dose Formulations
Dose formulations were stored at room temperature (20 ± 5 °C) protected from light in glass beakers.
Based upon the results of stability analyses performed within the RCC study no. B97031 (Validation of an analytical method for dose formulation analysis), dose formulations were stable for at least one week.


VEHICLE
- Amount of vehicle (if gavage): Dose Volume: 10 mL/kg body weight; daily adjustment to the actual body weight
- Purity: highly purified water
- Target does level: 0 mg/kg/day, 50 mg/kg/day, 200 mg/kg/day and 1000 mg/kg/day

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The samples were analyzed by IC coupled to a conductivity detector following an analytical procedure developed at Harlan Laboratories. The test item was used as the analytical standard. The following acceptance criteria was applied to analytical results: sample contents should be within a range of ±20% of nominal. Formulations were considered homogenous if the maximum deviation from mean calculated from top, middle and bottom samples was no more than 15%.
The results obtained from storage stability samples should not deviate more than 10% from timezero reference (content or mean of homogeneity samples).
In conclusion, the results indicate the accurate use of the test item Sodium 2-hydroxyethanesulphonate and highly purified water as vehicle during this study. Application formulations were found to be homogeneously prepared and sufficient formulation stability under storage conditions was approved.

Details on mating procedure:

- Impregnation procedure: After 7 days of acclimatization, females were housed with sexually mature males (1:1) in special automatic mating cages i.e. with synchronized timing to initiate the nightly mating period, until evidence of copulation was observed. This system reduced the variation in the copulation times of the different females. The females were removed and housed individually if:
a) The daily vaginal smear was sperm positive, or
b) A copulation plug was observed.

-Male rats of the same source and strain were used only for mating. These male rats are in the
possession of Harlan Laboratories and were not considered part of the test system. The fertility
of these males had been proven and was continuously monitored.

Duration of treatment / exposure:

Exposure period: Day 0 post coitum (first treatment) to day 20 post coitum (last treatment)

Frequency of treatment:

Daily

Duration of test:

Duration of Treatment Period: Day 0 - 20 post coitum

No. of animals per sex per dose:

22 mated females per group

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose levels were selected based on a previous dose range finding toxicity study in Han Wistar rats, Harlan Laboratories Study B96996, using dose levels of 100, 300 and 1000 mg/kg/day.
- Rationale for animal assignment (if not random):Computer-generated random algorithm

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Viability/mortality was observed twice daily. Cage-side clinical signs (once daily, during acclimatization and up to day of necropsy) were noted daily.
- Cage side observations : yes


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations:Body weights recorded daily from day 0 until day 21 post coitum.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption was recorded at 3-day intervals: days 0-3, 3-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post coitum.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations:


POST-MORTEM EXAMINATIONS: Yes
Maternal Data
- Sacrifice on gestation day # 21
Necropsy
The females were sacrificed by CO2 asphyxiation. Post mortem examination, including gross macroscopic examination of all internal organs with emphasis on the uterus, uterine contents, position of fetuses in the uterus and the number of corpora lutea was performed and the data recorded. The uteri (and contents) of all females with live fetuses were weighed during necropsy on day 21 post coitum to enable the calculation of the corrected body weight gain

OTHER: Fetus examinations: yes

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 resorptions: Yes
- Position of fetus: yes
Post mortem examination, including gross macroscopic examination of all internal organs with emphasis on the uterus, uterine contents, position of fetuses in the uterus and the number of corpora lutea was performed and the data recorded. The uteri (and contents) of all females with live fetuses were weighed during necropsy on day 21 post coitum to enable the calculation of the corrected body weight gain

Fetal examinations:

- Body weights of Live Fetuses: Yes: per dam
- External examinations: Yes: all per litter

Fetal Pathology
Fetuses were removed from the uterus, sexed, weighed individually, examined for gross external abnormalities, sacrificed by a subcutaneous injection of sodium pentobarbital and allocated to one of the following procedures:
1. Microdissection technique (sectioning/dissection technique). At least one half of the fetuses from each litter was fixed in Bouin's fixative (one fetus per container). They were examined by a combination of serial sections of the head and microdissection of the thorax and abdomen. This included detailed examination of the major blood vessels and sectioning of the heart and kidneys. After examination, the tissue was preserved in a solution of glycerin/ethanol (one fetus per container). Descriptions of any abnormalities and variations were recorded.
2. The remaining fetuses were eviscerated and with the exception of over the paws, the skin was removed and discarded. Carcasses were processed through solutions of ethanol, glacial acetic acid with Alcian blue (for cartilage staining), potassium hydroxide with Alizarin red S (for clearing and staining ossified bone) and aqueous glycerin for preservation and storage. The skeletons were examined and all abnormal findings and variations were recorded. The specimens were preserved individually in plastic vials.
If no implantation sites were evident, the uterus was placed in an aqueous solution of ammonium sulfide to accentuate possible hemorrhagic areas of implantation sites.

Statistics:

The following statistical methods were used to analyze food consumption, body weights and reproduction data:
• Means and standard deviations of various data were calculated.
• The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
• Fisher’s exact-test was applied if the variables could be dichotomized without loss of information.

Historical control data:

Historical control data of rats (WiIST Han/Brl (SPF Quality)); Dara from prenatal developmental toxicity studies, performed during 2004 and 2005; provided by: RCC Ltd., toxicology, 4414 Füllinsdorf / Switzerland

Reproduction data; spontaneous abnormal findings (external); abnormal findings from visceral examination of fetuses; abnormal findings and variations from skeletal and cartilage examinations of fetuses-summary; skeletal examination of fetuses (stage of development): fetus basis and litter basis; cartilage examination of fetuses (stage of development and variations): fetus basis and litter basis

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
All dams survived until the scheduled necropsy. No clinical symptoms or observations were noted during the study in any groups.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Remarks on result:

not determinable due to absence of adverse toxic effects

Fetal body weight changes:

no effects observed

Changes in sex ratio:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Clinical Signs or Observations - Females

 

	Group 1 0 mg/kg	Group 2 50 mg/kg	Group 3 200 mg/kg	Group 4 1000 mg/kg
Number of females examined	22	22	22	22
No clinical signs or observations	22	22	22	22

Summary of Performance of Mated Females

Group	1	2	3	4
Dose (mg/kg)	(0)	(50)	(200)	(1000)
Female numbers	1 - 22	23 - 44	45 - 66	67 - 88
Number of mated females	22	22	22	22
Number of females with live fetuses at termination*	22	22	22	22

* Only dams with at least one live fetus at Caesarean section were used for the calculations of food consumption, body weight gain and corrected body weight gain data.

Maternal Data

Clinical Signs or Observations

All dams survived until the scheduled necropsy. No clinical symptoms or observations were noted during the study in any groups.

Food Consumption

In group 4, mean food consumption was marginally lower than control (-4.3% compared to the control group). Since this was not statistically significant and in absence of an effect on body weight was considered to be of no toxicological relevance. In groups 2 and 3, mean food consumption was similar to the control group (±0.0% and +0.4% compared to the control group, respectively).

Body Weights

Mean body weight and mean body weight gain were not considered to be affected by the treatment with the test item. Corrected body weight gain (corrected for the weight of the gravid uterus) was not considered to be affected by the treatment with the test item (15.8%, 14.1%, 14.9% and 14.0% in groups 1, 2, 3 and 4, respectively).

Reproduction Data

No test item-related effects on the reproduction data (pre-implantation loss, number of implantation sites, post-implantation loss and mean number of fetuses per dam) were noted at any dose level. In group 3, post-implantation loss was statistically significantly higher. Consequently, the number of fetuses was statistically significantly lower compared to the control group. This was considered to be incidental since there was no dose-dependency and within the range of the historical control data.

Macroscopical Findings

No abnormal findings were noted during the necropsy examination.

Fetal Data

External Examination

No test item-related abnormal findings were noted. In group 4, one fetus was noted to have the lower mandible markedly shortened and with only one central nostril. A shortened lower mandible was also noted in one fetus in the control group. These findings were noted as isolated cases in single fetuses and thus considered not to be related to the treatment with the test item.

Sex Ratios

No test item-related effects on the sex ratio of the fetuses were noted in any group. The percentage of male fetuses was 49.3%, 51.4%, 50.6% and 47.7% in groups 1, 2, 3 and 4, respectively.

Body Weights

Mean fetal weights were not affected by treatment with the test item at any dose level.

Visceral Examination of Fetuses (Microdissection Technique)

During visceral examination of the fetuses, findings were noted in:

43% examined fetuses (in 100% litters) in group 1

51% examined fetuses (in 95% litters) in group 2

42% examined fetuses (in 95% litters) in group 3

38% examined fetuses (in 91% litters) in group 4

Abnormalities were noted in one fetus each in groups 1, 2 and 4 and were considered to be incidental. In group 1, one fetus was noted to have a small mouth and short tongue. In group 2, one fetus had thoracic situs inversus. In group 4, one fetus had small mouth, tongue absent, cleft and misshapen palate, fused nares, short nasal septum, interrupted and misshapen nasopharynx and small pituitary. These abnormalities occurred in single fetuses and did not give any indication of a test item-related effect.

The type and frequency of the noted variations were similar in all groups and did not indicate any dose-dependency. They were therefore considered not to be test item-related.

Skeletal Examinations of Fetuses (Abnormalities and Variations)

During skeletal examination of the fetuses, findings were noted in:

16% examined fetuses (in 59% litters) in group 1

8% examined fetuses (in 32% litters) in group 2

13% examined fetuses (in 45% litters) in group 3

13% examined fetuses (in 50% litters) in group 4

No test item-related findings were noted.

The type and frequencies of the noted less common variations were similar in nature for the group receiving the test item and the control group and did not indicate any dose-dependency, therefore they were not considered to be test item-related.

Bone and cartilage abnormalities were found in one fetus in group 3, which had right rib 1 short and left costal cartilage 1 short and right costal cartilage absent.

Bone Examination - Ossification Stage / Supernumerary Ribs

There were no test item-related effects on the ossification stage and the number of supernumerary ribs in any dose group.

The occasionally statistically significant differences did not show dose dependency and were caused by higher as well as lower stages of development, therefore were considered to be incidental.

Cartilage Examination - Additional Variations

During cartilage examination of the fetuses abnormal findings were noted in:

2% examined fetuses (in 14% litters) in group 1

4% examined fetuses (in 23% litters) in group 2

4% examined fetuses (in 18% litters) in group 3

4% examined fetuses (in 23% litters) in group 4

No test item-related findings were noted.

In group 4, statistically significantly higher incidence of branched xiphoid cartilage was noted when calculated on a litter basis. Since no statistically significance was noted when calculated on a fetus basis this finding was considered to be incidental.

Conclusions:

Based on the above mentioned results and taking into consideration that the reduction of food consumption was not statistically significant, the NOAEL (No Observed Adverse Effect Level) for maternal and fetal organisms was considered to be 1000 mg/kg body weight/day.

Under the conditions described for this study, 2-Hydroxyethanesulphonate did not reveal teratogenic potential up to and including 1000 mg/kg body weight/day.

Executive summary:

The purpose of this study was to detect effects on the pregnant rat and development of the embryo and fetus consequent to exposure of the female to the test item from day 0 post coitum (implantation) to day 20 post coitum (the day prior to Caesarean section).

Four groups of females were treated by gavage with Sodium 2-Hydroxyethanesulphonate once daily at dose levels of:

Group 1: 0 mg/kg body weight/day (control group)

Group 2: 50 mg/kg body weight/day

Group 3: 200 mg/kg body weight/day

Group 4: 1000 mg/kg body weight/day

A standard dose volume of 10 mL/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle alone (highly purified water).

All females were sacrificed on day 21 post coitum and the fetuses were removed by Caesarean section.

The following results were obtained:

1. Maternal Data

General Tolerability

All dams survived until the scheduled necropsy. No clinical symptoms related to treatment with the test item were noted during the study.

Food Consumption and Body Weights

Food consumption and body weight were not affected by the treatment with the test item. At 1000 mg/kg/day, mean food consumption was marginally lower than control, but as it was not statistically significant and in absence of an effect on body weight was considered to be of no toxicological relevance.

Reproduction Data

The relevant reproduction data (pre- and post-implantation loss and the mean number of fetuses per dam) were not affected by treatment with the test item at any dose level.

Macroscopical Findings

No macroscopical findings were noted during necropsy of the dams.

2. Fetal Data

External Examination

The abnormal findings observed during the external examinations were considered to be incidental since they occurred isolated in single fetuses.

Sex Ratios

No test item-related effects on fetal sex ratios were noted in any dose group.

Body Weights

No test item-related effects on fetal body weights were noted.

Visceral Examination

No test item-related abnormalities were noted during the visceral examination of fetuses.

Skeletal and Cartilage Examination

No abnormalities, which were considered to be test item-related, were noted during examination of fetal skeletons and cartilages.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available study was concluded to be reliable (Klimisch 1 study).

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Toxicity to reproduction: other studies

Additional information

In accordance with Section 1.2 of REACH Annex XI, there is sufficient weight of evidence from several independent sources of information leading to the conclusion that Sodium 2-hydroxyethansulphonate does not cause toxicity to reproduction and/or development and thus SI does not have to be classified:

- Sodium 2-hydroxyethansulphonate caused no effects on reproductive organs in a 90-day oral gavage study in rats up to and including the highest dose tested (1000 mg/kg/day);

- Sodium 2-hydroxyethansulphonate did not cause any maternal or developmental effect in a developmental study in rats (NOAEL = 1000 mg/kg bw/day);

- Sodium 2-hydroxyethansulphonate showed no bioactivity in a combination of assays representing extensive biological coverage for molecular processes underpinning human reproduction and embryonic development.

 

It can therefore be concluded with sufficient certainty that Sodium 2-hydroxyethansulphonate will not cause toxicity to reproduction and that further aninal testing is not scientifically necessary.

 

In addition it is considered that the developmental toxicity of Sodium 2-hydroxyethansulphonate was evaluated in rats according to OECD guideline 414 study and GLP. No maternal and developmental effects were observed up to 1000 mg/kg bw/d.

 

Therefore, it is concluded that Sodium 2-hydroxyethansulphonate is not subject to classification and labelling according to Directive 67/548/EEC and Regulation 1272/2008/EC regarding reproductive and developmental toxicity.

Justification for classification or non-classification

Based on the full data-set of Sodium 2-hydroxyethansulphonate SI is not subject to classification and labelling for reproductive and developmental toxicity according to Regulation 1272/2008/EC .