Ammonium sulphamidate

Endpoint summary

Description of key information

Based on the read-across on sodium sulphamidate, ammonium sulphamidate is not acutely toxic by the oral or dermal route in the rats.

-Acute oral toxicity: The acute oral median lethal dose (LD50) of sodium sulphamidate in the female Wistar strain rat was estimated to be greater than 2500 mg/kg bodyweight
-Acute dermal toxicity: The acute dermal median lethal dose (LD50) of sodium sulphamidate in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

The study was performed between 28 June 2011 and 26 July 2011.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 2000

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Female Wistar (RccHan:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK.
- Age at study initiation: Eight to twelve weeks of age
- Weight at study initiation: 157 - 184 g (bodyweights fell within an interval of ±20% of the mean initial bodyweight of the first treated group).
- Fasting period before study: Overnight fast immediately before dosing and for approximately three to four hours after dosing
- Housing: The animals were housed in groups of three in suspended solid floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): Food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study.
- Water (e.g. ad libitum): Free access to mains drinking water was allowed throughout the study.
The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.
- Acclimation period: At least five days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Set to achieve limits of 19 to 25°C
- Humidity (%): Set to achieve limits of 30 to 70%
Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study.
- Air changes (per hr): At least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 mg/ml or 200 mg/ml


MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

DOSAGE PREPARATION: The test item was freshly prepared, as required, as a solution at the appropriate concentration in distilled water.
The test item was formulated within two hours of being applied to the test system. It is assumed that the formulation was stable for this duration.


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:
In the absence of data regarding the toxicity of the test item, 300 mg/kg was chosen as the starting dose.

Doses:

300 mg/kg and 2000 mg/kg

No. of animals per sex per dose:

3 females at 300 mg/kg.
6 females at 2000 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for up to fourteen days.
Individual bodyweights were recorded prior to dosing and seven and fourteen days after treatment.

- Necropsy of survivors performed: yes; At the end of the observation period the surviving animals were killed by cervical dislocation. All animals were subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 500 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths at 300 mg/kg bw or 2000 mg/kg bw

Clinical signs:

other: There were no signs of systemic toxicity at 300 mg/kg bw or 2000 mg/kg bw

Gross pathology:

No abnormalities were noted at necropsy at 300 mg/kg bw or 2000 mg/kg bw

Individual Bodyweights and Weekly Bodyweight Changes - 300 mg/kg

Dose Level mg/kg	Animal Number and Sex	Bodyweight (g) at Day			Bodyweight Gain (g) During Week
		0	7	14	1	2
300	1-0 Female	184	200	205	16	5
	1-1 Female	183	190	199	7	9
	1-2 Female	174	194	204	20	10

Individual Bodyweights and Weekly Bodyweight Changes - 2000 mg/kg

Dose Level mg/kg	Animal Number and Sex	Bodyweight (g) at Day			Bodyweight Gain (g) During Week
		0	7	14	1	2
2000	2-0 Female	180	186	196	6	10
	2-1 Female	171	191	201	20	10
	2-2 Female	175	183	197	8	14
	3-0 Female	167	177	187	10	10
	3-1 Female	174	180	196	6	16
	3-2 Female	157	166	178	9	12

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2500 mg/kg bodyweight

Executive summary:

Introduction.

The study was performed to assess the acute oral toxicity of the test item following a single oral administration in the Wistar strain rat. The method was designed to be compatible with the following:

- OECD Guidelines for the Testing of Chemicals No. 423 “Acute Oral Toxicity – Acute Toxic Class Method” (adopted 17 December 2001)

- Method B1 tris Acute Toxicity (Oral) of Commission Regulation (EC) No. 440/2008

- United States Environmental Protection Agency Health Effects Test Guidelines OPPTS 870.1100 Acute Oral Toxicity, 2002

- Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 2000

Method. 

A group of three fasted females was treated with the test item at a dose level of 300 mg/kg bodyweight. Based on the results from this dose level further groups of fasted females were treated at a dose level of 2000 mg/kg bodyweight. Dosing was performed sequentially.

The test item was administered orally as asolution in distilled water. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. 

There were no deaths.

Clinical Observations. 

There were no signs of systemic toxicity.

Bodyweight. 

All animals showed expected gains in bodyweight over the study period.

Necropsy. 

No abnormalities were noted at necropsy.

Conclusion. 

The acute oral median lethal dose (LD₅₀) of the test item in the female Wistar strain rat was estimated to be greater than 2500 mg/kg bodyweight (Globally Harmonised Classification System ‑ Unclassified).

The test item did not meet the criteria for classification according to the Classification, Labelling and Packaging Regulation (CLP).

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

sodium sulphamidate

Adequacy of study:

weight of evidence

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
A read across, based on analogue approach, has been performed between ammonium sulphamidate EC 231-871-7 (target chemical) and sodium sulphamidate EC 237-572-8 (source chemical).
The read-across hypothesis, according to Read Across Assessment Framework published by ECHA, is based on the fact that different compounds which have the same type of effect(s). It corresponds to the scenario 2 described as follows:
« This scenario covers the analogue approach for which the read-across hypothesis is based on different compounds which have the same type of effect(s). For the REACH information requirement under consideration, the effects obtained in a study conducted with one source substance are used to predict the effects that would be observed in a study with the target substance if it were to be conducted. The same type of effect(s) or absence of effect is predicted. The predicted strength of the effects may be similar or based on a worst case assumption. »

1) Chemical structure
The target and source substances share the same anionic structure, i.e. a sulphamidate (formula: –OSO2NH2). They only differ by the positive counter ion: an ammonium ion (NH4+) for the target substance and a sodium ion (Na+) for the source substance. It is well known that usually, the counter ion has no impact on the toxicity profile of the substance. For this reason, the QSARs are classically performed on the “core” of the salt and do not consider the counter ion.
See the structures in attached justification.

2) Kinetics
Ammonium sulphamidate
The substance is highly water soluble, meaning its ions dissolve in water. Following oral administration of ammonium sulfamate to dogs for 5 days, 80 to 84% of the dose was excreted as sulfamic acid in the urine, indicating that ammonium sulfamate is readily absorbed into the bloodstream from the gastrointestinal tract. (Pesticide Active Ingredient Information – EXTOXNET)

Sodium sulphamidate
Absorption of sodium sulphamidate from the gastrointestinal tract is supported by the repeated dose reproductive screening study in rats. The high water solubility and small molecular size of sodium sulphamidate allow absorption through passive diffusion. This would suggest that the gastro-intestinal tract provides a route of absorption, following oral administration, before entering the circulatory system via the blood.
Absorption of sodium sulphamidate may also take place via the skin due to small molecular size and water solubility. Although the substance is not a skin sensitizer there is evidence of mild dermal irritation. Therefore damage to the skin surface may allow for increased penetration of the substance through the skin.

Once absorbed, the substance would be distributed in the serum due to the water solubility.

The results of the repeated dose reproductive screening study would suggest that the most likely route of excretion is the kidney due to the likely systemic distribution and water solubility of the test item. Any test item that is not absorbed will be excreted in the faeces. [ECHA’s registration dossier of sodium sulphamidate].

Conclusion
Both substances are absorbed via oral route and are found excreted in urine. Inhalation exposure is not relevant due to the low vapour pressure of each substance.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
1) Physical and chemical information
The physico-chemical properties were compared between the target and the source substance. Synthron data are in blue and Nalco data (found in ECHA’s registration dossier of sodium sulphamidate) are in green. Published data are in purple and other data are in black (please refer to the comparative table in attached justification).

Both substances share some common physico-chemical properties: white solid appearance, decomposition, high partition coefficient, negligible vapour pressure, absence of surface activity, good water solubility, absence of flammability/explosive and oxidizing properties.
Some physico-chemical differences can be highlighted between the two substances: the different molecular weight is attributed to the counter-ion. The boiling and melting points are slightly different as well as the relative density. The dissociation constants vary due to the different counter-ions which cannot be used for the read-across proposal. In this case, the sulphamidic acid is the most appropriate substance. The pKa values around 1.0 (0.9 or 0.997 or 1.05 as found in the "Handbook of Chemistry and Physics", 85th ed.) all refer to the free acid, sulphamidic acid. Ammonium sulphamate contains as cation the ammonium ion with a pKa of 9.25 ("Handbook of Chemistry and Physics", 85th ed.) Any attempt of coming into the region of pH that is near the pKa of the primary amine group (13.6 ± 0.6) would cause the deprotonation of the ammonium ion and the transformation of the target chemical into the respective alkaline metal salt, for instance sodium sulphamidate. Therefore, the pKa of the primary amine group in the sulphamidate anion reported in the sodium sulphamidate dossier is not relevant for ammonium sulphamidate.
Therefore, both substances share many common physico-chemical features, and the observed differences can be attributed to the different counter-ion.

2) Toxicological and ecotoxicological information
The ammonium ion of the target substance may contribute to the toxicity of ammonium sulphamidate, compared to sodium sulphamidate. However, as both substances are highly water soluble, their ions dissolve in water. Therefore, the ammonium ion is no more a concern.
Please refer to the comparative table in attached justification.

Regarding the toxicity endpoints, some common points are shared by the two substances: low acute toxicity by oral route, no mutagenicity in bacteria, mild to no skin or eye irritation. Some differences occurred in the systemic toxicity study: in the repeated dose toxicity study, the NOAEL are not the same between sodium (NOAEL = 1000 mg/kg bw/d) and ammonium sulphamidate (NOEL = 214.3 mg/kg bw/d). In the reproductive study, NOEL for ammonium sulphamidate was found to be 25 mg/kg bw/d in the literature whereas the NOAEL for sodium sulphamidate is 1000 mg/kg bw/d. However, these differences must be considered with caution as the experimental protocols differ.

As for the ecotoxicity endpoints, both substances seem not to be toxic to fish, based on their LC50 > 100 mg/L (LC50 of at least 650 mg/L).

Last, the environmental fate data on both substances indicate that they are likely to be adsorbed into the soil. Their half-life differ as sodium sulphamidate is very stable (half-life > 1 year) and ammonium sulphamidate may be less stable (half-life of 14 days, based on a published data).


3) Classification proposal
The sodium sulphamidate is not classified in ECHA’s registration dossier. Based on the read-across approach, ammonium sulphamidate would not be classified either.

3. ANALOGUE APPROACH JUSTIFICATION
Based on the available elements, it can be assumed that ammonium and sodium sulphamidate may have close kinetic profiles, physico-chemical, toxicological and ecotoxicological properties. The read-across approach is therefore relevant.

Reason / purpose for cross-reference:

read-across source

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 500 mg/kg bw

Based on:

test mat.

Interpretation of results:

not classified

Conclusions:

Based on the read across on sodium sulphamidate, the acute oral lethal dose (LD50) of ammonium sulphamidate in the female Wistar strain rat was estimated to be greater than 2500 mg/kg bodyweight

Endpoint conclusion

Dose descriptor:

LD50

Value:

2 500 mg/kg bw

Acute toxicity: via dermal route

Endpoint conclusion

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Acute Oral Toxicity.

Introduction.

The study was performed to assess the acute oral toxicity of sodium sulphamidate following a single oral administration in the Wistar strain rat. The method was designed to be compatible with the following:

- OECD Guidelines for the Testing of Chemicals No. 423 “Acute Oral Toxicity – Acute Toxic Class Method” (adopted 17 December 2001)

- Method B1 tris Acute Toxicity (Oral) of Commission Regulation (EC) No. 440/2008

- United States Environmental Protection Agency Health Effects Test Guidelines OPPTS 870.1100 Acute Oral Toxicity, 2002

- Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 2000

Method. 

A group of three fasted females was treated with the test item at a dose level of 300 mg/kg bodyweight. Based on the results from this dose level further groups of fasted females were treated at a dose level of 2000 mg/kg bodyweight. Dosing was performed sequentially.

The test item was administered orally as asolution in distilled water. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. 

There were no deaths.

Clinical Observations. 

There were no signs of systemic toxicity.

Bodyweight. 

All animals showed expected gains in bodyweight over the study period.

Necropsy. 

No abnormalities were noted at necropsy.

Conclusion. 

The acute oral median lethal dose (LD₅₀) of the test item in the female Wistar strain rat was estimated to be greater than 2500 mg/kg bodyweight.

Acute Dermal Toxicity

Introduction. 

The study was performed to assess the acute dermal toxicity of sodium sulphamidate in the Wistar strain rat. The method was designed to be compatible with the following:

-      OECD Guidelines for the Testing of Chemicals No. 402 “Acute Dermal Toxicity” (adopted 24 February 1987)

-      Method B3 Acute Toxicity (Dermal) of CommissionRegulation (EC) No. 440/2008

- United States Environmental Protection Agency Health Effects Tesat Guidelines OPPTS 870.1200 Acute Dermal Toxicity August 1998

- Japanese Ministry of Agriculture, Forestry and Fisheries (MAFF), Testing Guidelines for Toxicology Studies, 12 NohSan No. 8147, amended 26 June 2001

- Japanese Ministry of Health and Welfare, 1992

Method. 

A group of ten animals (five males and five females) was given a single, 24 hour, semi‑occluded dermal application of the test item to intact skin at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. 

There were no deaths.

Clinical Observations. 

There were no signs of systemic toxicity.

Dermal Irritation. 

There were no signs of dermal irritation.

Bodyweight. 

Animals showed expected gains in bodyweight over the study period, except for three females which showed bodyweight loss during the first week but expected gain in bodyweight during the second week.

Necropsy. 

No abnormalities were noted at necropsy.

Conclusion. 

The acute dermal median lethal dose (LD₅₀) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

Acute Inhalation Toxicity:

Inhalation is not considered a significant route of exposure and a study has therefore not been conducted.

Justification for classification or non-classification

The substance does not meet the criteria for classification for acute toxicity via the oral or dermal results based on the results of an acute oral toxicity study and an acute dermal toxicity study, which gave LD₅₀ results of >2500 mg/kg bodyweight and >2000 mg/kg bodyweight respectively.