Disodium succinate

Disodium Succinate(Anhydrous)

Molecular formula,anhydride:C4H4Na2O4
Molecular weight:162.06
Property:crystal white crystal granules;anhydride is crystal powder; odorless,no acid taste, taste threshold 0.03%; at 120, it will loose crystal water and become anhydride;easily soluble in water,insoluble in ethanol; stable in the air.
Quality index:In accordance with Q/SS02-2005 standard
Specification:Assay98%

PH-value,5% water solution7-9

Arsenic(As2O3)2PPM

Heavy metal (Pb)10PPM

Sulphate (SO2-4)0.019%

Potassium permanganate reducing substancesQualified

Drying loss (120, 3h)2%

Use:As flavoring agent, buffering agent.
Packing:25kg woven bag with plastic lining.

Disodium Succinate(Hexahydrate)

Molecular formula:C4H4Na2O46H2O
Molecular weight:270.15e
Property:crystal white crystal granules;anhydride is crystal powder; odorless,no acid taste, taste threshold 0.03%; at 120, it will loose crystal water and become anhydride;easily soluble in water,insoluble in ethanol; stable in the air.
Quality index:Q/SS02-2005
Specification:Assay98-101%

PH-value,5% water solution7-9

Arsenic(As2O3)2PPM

Heavy metal (Pb)10PPM

Sulphate (SO2-4)0.019%

Potassium permanganate reducing substancesQualified

Loss on drying37-41%

Use:As flavoring agent, buffering agent.
Packing:25kg woven bag with plastic lining.

SIDS Initial Assessment Report

For

SIAM 16

Paris, France, 27-30 May 2003 

1. Chemical Name: Disodium succinate

2. CAS Number: 150-90-3

3. Sponsor Country: Japan

Contact Point:

Mr. Yasuhisa Kawamura

Director

Second International Organizations Division

Ministry of Foreign Affairs, Japan

4. Shared Partnership with:

5. Roles/Responsibilities of

the Partners:

x Name of industry sponsor

/consortium

x Process used

6. Sponsorship History

x How was the chemical or

category brought into the

OECD HPV Chemicals

Programme ?

The original draft documents were prepared by the Japanese

government.

7. Review Process Prior to

the SIAM:

8. Quality check process:

9. Date of Submission: 21 February, 2003

10. Date of last Update:

11. Comments: 

SIDS INITIAL ASSESSMENT PROFILE

CAS No. 150-90-3

Chemical Name Disodium succinate

Structural Formula NaOOCCH2CH2COONa 

SUMMARY CONCLUSIONS OF THE SIAR

Analogue Rationale

Disodium succinate is stable as a hexahydrate and has been produced as disodium succinate hexahydrate (CAS No.:6106-21-4) in Japan. Many toxicity studies were conducted using disodium succinate hexahydrate as the test substance, because there should be no difference between disodium suucinate and disodium succinate hexahydrate in

terms of environmental behavior, aquatic toxicity, and mammalian toxicity.

Human Health

There is no available information on toxicokinetics and metabolism.

An oral acute toxicity study [OECD TG 401] of disodium succinate hexahydrate showed that this chemical did not cause any changes even at 2,000 mg/kg. The oral LD50 value was considered to be greater than 2,000 mg (equivalent to 1,200 mg of disodium succinate)/kg bw in male and female rats.

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [OECD TG 422], Crj: CD (SD) IGS rats were given disodium succinate hexahydrate by gavage at 0, 100, 300, or 1,000 mg/kgbw/day. Males were dosed for 52 days from day 14 before mating and females were dosed from day 14 before mating to day 4 of lactation throughout the mating and pregnancy period. Blood urea nitrogen levels were increased in females at 1,000 mg/kg bw/day. Higher levels of urinary protein were found in one and two of the five males at 300 and 1,000 mg/kg bw/day, respectively, whereas no animals with these high levels were found in the control and 100 mg/kg bw/day groups. These findings suggest adverse effects of this compound on the kidney. Therefore, the NOAEL of disodium succinate hexahydrate for repeated dose toxicity was considered to be 100 mg (equivalent to 60 mg of disodium succinate)/kg bw/day for male rats and 300 mg (equivalent to 180 mg of disodium succinate)/kgbw/day for female rats.

In a reverse gene mutation assay [OECD TG 471], disodium succinate hexahydrate was not mutagenic in Salmonella typhimurium TA98, TA100, TA1535, and TA1537, and Escherichia coli WP2 uvrA with and without an exogenous metabolic activation. In a chromosomal aberration test [OECD TG 473], disodium succinate hexahydrate did not induce structural chromosomal aberrations or polyploidy with and without an exogenous metabolic activation in cultured Chinese hamster lung (CHL/IU) cells.

There is no data available on the carcinogenicity.

The above-mentioned combined study [OECD TG 422] showed that the reproduction/developmental parameters, i.e.,mating, pregnancy, delivery, lactation, and viability and body weight of pups, were not affected by disodium succinate hexahydrate at up to 1,000 mg/kg bw/day. The NOAEL of disodium succinate hexahydrate for reproduction/developmental toxicity was considered to be 1,000 mg (highest dose tested, equivalent to 600 mg of disodium succinate)/kg bw/day in rats.

There is no available information on eye and skin irritation and sensitization.

Environment

Disodium succinate is a white powder with a melting point of more than 400 degree C, a water solubility of more

than 100 g/L. This chemical is stable at pH 4,7and 9 at 50 degree C for 5 days, and readily biodegradable. A vapour pressure of 1.16x10-5 Pa is calculated. A Log Pow of < -0.59 is estimated and the bioaccumulation potential of disodium succinate is expected to be low.

The toxicity of disodium succinate on aquatic organisms has been studied in three freshwater species belonging to three trophic levels. The toxicity tests were conducted using disodium succinate hexahydrate instead of the test substance because disodium succinate hexahydrate is not different to the test substance in aqueous solution and disodium succinate is stable as hexahydrate.

In an algal growth inhibition test (OECD TG 201, Selenastrum capricornutum, open system), the 72 h ErC50 and the 72 h EbC50 were >998 mg/L. For daphnids, a 48 h EC0 of 997 mg/L and a 48 h EC50 > 997 mg/L were reported (OECD TG 202, Daphnia magna, static). For fish (OECD TG 203, Oryzias latipes, flow-through) a 96 h LC0 of 47.0 mg/L, 96 h LC50 >95.4 mg/L and 96 h LC100 > 95.4 mg/L were determined.

Regarding chronic toxicity to algae, a 72 h NOErC of 998 mg/L and a NOEbC 998 mg/L (OECD TG 201,Selenastrum capricornutum, open system) were reported. For daphnids, the 21 d EC50 was more than 95.2 mg and a 21 d NOEC of 95.2 mg/L on reproduction and a 21 d LC50 >95.2 mg/L for parent daphnids were reported (OECD TG 211, Daphnia magna, semi-static).

There is no information available on toxicity to terrestrial or other organisms.

Exposure

Disodium succinate anhydrate and hexahydrate is used as a seasoning agent and raw material for plating reagent.This chemical is permitted for use as a food additive and no limit value for food additives exists in Japan. This chemical is naturally contained in shellfish. In Japan disodium succinate is being produced in its hexahydrate form and the annual production volume in Japan is ca. 3,000 tonnes.

The main target environmental compartment of this chemical is water and once it is released into the aquatic phase,partitioning to other compartments is unlikely to occur.Occupational exposure to this chemical through inhalation and dermal routes is possible. Consumer exposure to this chemical through ingestion is possible.

RECOMMENDATION

The chemical is currently of low priority for further work. 

RATIONALE FOR THE RECOMMENDATION AND

NATURE OF FURTHER WORK RECOMMENDED

The chemical is currently of low priority for further work based on its low hazard potential. 

SIDS Initial Assessment Report

1 IDENTITY

1.1 Identification of the Substance

CAS Number: 150-90-3

Chemical Name: Disodium succinate

Molecular Formula: C4H4Na2O4

Structural Formula: NaOOCCH2CH2COONa

Synonyms: Butanedioic acid disodium salt

Di-sodium succinate

Disodium succinate

Sodium succinate

Succinic acid, disodium salt

Succinic acid disodium salt

Succinic acid sodium salt

Soduxin

Substance type: organic

Physical status: powder

1.2 Purity/Impurities/Additives

Purity: 100% (titration by HClO4)

1.4 Analogue rationale

Disodium succinate is stable as a hexahydrate and has been produced as disodium succinate hexahydrate (CAS No.: 6106-21-4) in Japan. Many toxicity studies were conducted using disodium succinate hexahydrate as the test substance, because there should be no difference between 

OECD SIDS DISODIUM SUCCINATE 6 UNEP PUBLICATIONS disodium suucinate and disodium succinate hexahydrate in terms of environmental behavior,aquatic toxicity, and mammalian toxicity. 

2 GENERAL INFORMATION ON EXPOSURE

2.1 Production Volumes and Use Pattern

This chemical is produced as hexahydrate (CAS No. 6106-21-4) in Japan. The production of CAS No. 6106-21-4 is 3,000 tons/year in Japan.In Japan, this chemical is used as a seasoning agent or as a raw material for plating reagent. It is added as a seasoning agent to sake (Japanese wine), soy sauce, boiled fish paste, ham, cracker and wasabi preserved in sake lees. In Europe, this chemical is not approved as a food additive but is registered as a flavouring agent.

2.2 Environmental Exposure and Fate

Disodium succinate dissociates in water releasing two sodium ions with two pKa values of 4.2 and 5.6 (CERI, 2000).A study on hydrolysis was conducted and no abiotic degradation was reported (pH 4, 7 and 9 at 50C over 5 days).

Disodium succinate is readily biodegradable (64 - 78% of BOD, 100% of HPLC and 100% of TOC were observed after 14 days in a test according to OECD TG301C). The estimated LogPow is less than -0.59. The BCF is estimated to be low according to the low LogPow value.

This chemical degrades by photochemically induced OH radicals in the atmosphere with a half-life of 360 hours. No estimation for the reaction with ozone is possible. The Henrys Law constant is estimated to be 5.45 x 10-12 atm m3/mol. Vapor pressure is less than 0.015 Pa at 100 C and is estimated to be 1.16 x 10-5 Pa at 25 C. The water solubility is more than 100 g/L at 25 C.

The main target environmental compartment of this chemical is water and, based on fugacity model(Mackay level III), once this chemical is released into the aquatic phase partitioning to other

compartment is unlikely to occur.

2.3 Occupational Exposure

In Japan, this chemical is synthesized by hydrogenation of maleic anhydride. Production processes,hydrogenation with hydrogen, neutralization with sodium hydroxide, purification and crystallization, and drying are performed in closed batch systems with remote control and the possibility of worker exposure to this chemical in these processes is very low.

During the packing process of this chemical under local exhaust ventilation, worker exposure through inhalation of dust is possible, since this chemical is non-volatile. The EHEinh for a worker during the packing operation (the duration is 6.5 hours/day) is estimated to be 0.06 mg/kg/day using the EASE model, assuming that this work is performed through direct handling under local exhaust ventilation, and that succinic acid easily aggregates. The EHEder for the worker during the same packing operation is 7.8 mg/kg/day, assuming that dermal contact to both hands is incidental. As the workers wear gloves, goggles, and dust masks during the packing operation, the actual exposure is probably less than these values.No occupational exposure standard value for this chemical was located.

3 HUMAN HEALTH HAZARDS

3.1 Effects on Human Health

Many toxicity studies were conducted using disodium succinate hexahydrate (CAC No. 6106-21-4),because there should be no difference between disodium succinate and disodium succinate hexahydrate in mammalian toxicity.

Disodium succinate (CAS No. 150-90-3) and disodium succinate hexahydrate (CAS No. 6106-21-4) were assessed. The NOAEL of disodium succinate hexahydrate was converted into the NOAEL of disodium succinate based on the molecular weights of each chemical.

3.1.1 Toxicokinetics, Metabolism and Distribution There is no data available.

3.1.2 Acute Toxicity

Studies in Animals

An acute toxicity study in rats was identified as a key study because it was well conducted according to an OECD acute oral toxicity test guideline [TG 401] [MHLW, Japan: 2002] under GLP (Table 2).

In this study, Crj:CD (SD) rats (five animals/sex/group) were administered disodium succinate hexahydrate by gavage at a single dose of 0 (vehicle: distilled water) or 2,000 mg/kg bw. No deaths or abnormal findings were found in any groups. There was no difference in body weight gain between groups. The oral LD50 value was considered to be greater than 2,000 mg/kg bw in male and female rats (2,000 mg of disodium succinate hexahydrate is equivalent to 1,200 mg of disodium succinate ).

Studies in Humans

There is no available information on humans.

Conclusion

The oral LD50 value was considered to be greater than 2,000 mg/kg bw in male and female rats(2,000 mg of disodium succinate hexahydrate is equivalent to 1,200 mg of disodium succinate ). 

3.1.3 Repeated Dose Toxicity

Studies in Animals

One study is available for repeated dose toxicity. This study was conducted according to an OECD combined repeated dose toxicity study with the reproduction/developmental toxicity screening test guideline [TG 422] [MHLW, Japan, 2002] under GLP. This study was identified as a key study because it was well conducted. The details of this study are as follows. 

OECD SIDS DISODIUM SUCCINATE

UNEP PUBLICATIONS 9

Crj: CD (SD) IGS rats (12 animals/sex/dose) were administered disodium succinate hexahydrate by gavage at doses of 0 (vehicle: distilled water), 100, 300, or 1,000 mg/kg bw/day. Males were dosed for 52 days from day 14 before mating and females were dosed from day 14 before mating to day 4 of lactation throughout the mating and pregnancy period. Hematological, blood biochemical, and histopathological examinations were performed in both sexes, and urinalysis was conducted in males.

No deaths were found in any groups. Slight loose stool was observed in one and four males at 100 and 1,000 mg/kg bw/day, respectively, and one female at 1,000 mg/kg bw/day. Salivation was found in one male and one female at 1,000 mg/kg bw/day. There were no effects of this compound on the body weight, food consumption, hematology, or blood coagulation. The blood sodium levels were higher in males at 300 and 1,000 mg/kg bw/day. The blood urea nitrogen levels were increased in females at 1,000 mg/kg bw/day. Higher levels (300 mg/dL and higher) of urinary proteins were found in one and two of the five males at 300 and 1,000 mg/kg bw/day, respectively,whereas no animals with these high levels were found in the control and 100 mg/kg bw/day groups.These findings suggest adverse effects of this compound on the kidney. Increased weight of the adrenal gland was observed in males at 1,000 mg/kg bw/day. No compound-related effects on the histopathological findings were observed. Based on the higher levels of urinary protein in males

and blood urea nitrogen in females, the NOAEL of disodium succinate hexahydrate for repeated dose toxicity was considered to be 100 mg/kg bw/day for male rats and 300 mg/kg bw/day for female rats (100 and 300 mg of disodium succinate hexahydrate are equivalent to 60 and 180 mg of disodium succinate , respectively).

Studies in Humans

There is no available information on humans.

Conclusion

In an oral repeated dose toxicity study in rats, higher levels of urinary protein in males and blood urea nitrogen in females were observed at 300 and 1,000 mg/kg bw/day, respectively. The NOAEL of disodium succinate hexahydrate for repeated dose toxicity was considered to be 100 mg/kg bw/day for male rats and 300 mg/kg bw/day for female rats (100 and 300 mg of disodium succinate hexahydrate are equivalent to 60 and 180 mg of disodium succinate , respectively). 

In vitro bacterial tests

Three studies were reported (Table 3). No positive results were obtained. The study by MHLW,Japan (2002) was identified as a key study because this study was well conducted according to a current protocol [OECD TG 471; Japanese Guideline for Screening Mutagenicity Testing Chemicals (Chemical Substances Control Law of Japan)] under GLP. Disodium succinate hexahydrate was not mutagenic with and without S9 mix in Salmonella typhimurium TA98, TA100,TA1535, and TA1537, and Escherichia coli WP2 uvrA at up to 5,000 g/plate (5,000 g of disodium succinate hexahydrate is equivalent to 3,000 g of disodium succinate). These results were supported by the results of Ishidate et al. (1984) and Fujita et al (1994).

Non-bacterial in vitro test

Two non-bacterial in vitro tests were reported (Table 4). Although Ishidate et al. (1984) reported an equivocal result (5% of polyploidy) at the very high concentration of 15,000 g/mL, no detailed information on the test procedures was available. MHLW, Japan (2002) conducted a chromosomal aberration test using cultured Chinese hamster lung (CHL/IU) cells according to OECD TG 473 under GLP. This study was identified as a key study because all experimental conditions and reporting were sufficient. Disodium succinate hexahydrate did not induce structural chromosomal aberrations and polyploidy with and without S9 mix at up to 5,000 g/mL (5,000 gof disodium succinate hexahydrate is equivalent to 3,000 g of disodium succinate). No cytotoxicity was observed at up to 5,000 g/mL after 6h short-term or 24-48h continuous treatment.

In vivo Studies

There is no available information. 

Conclusion

Disodium succinate was not genotoxic with and without an exogenous metabolic activation in bacterial tests as well as a chromosomal aberration test in vitro.

3.1.5 Carcinogenicity

There are no data available.

3.1.6 Reproduction/developmental toxicity

Studies in Animals

One study is available for reproductive and developmental toxicity. This study was conducted according to an OECD combined repeated dose toxicity study with the reproduction/developmental toxicity screening test guideline [TG 422] [MHLW, Japan: 2002] under GLP. This study was identified as a key study because it was well conducted. Details of the study are as follows.

Crj: CD (SD) IGS rats (12 animals/sex/dose) were administered disodium succinate hexahydrate by gavage at doses of 0 (vehicle: distilled water), 100, 300, or 1,000 mg/kg bw/day. Males were dosed for 52 days from day 14 before mating and females were dosed from day 14 before mating to day 4 of lactation throughout the mating and pregnancy period. No compound-related effects on the estrous cycle, copulation index, fertility index, gestation length, gestation index, number of corpora lutea, or number of implantation sites were found in dams. No compound-related effects on the number, sex ratio, or viability were observed in pups on days 0 and 4 of lactation. Anophthalmia and polydactyly were observed in one pup at 300 mg/kg bw/day. These anomalies are considered to be spontaneous, because the incidences of these anomalies were extremely low and these are of

types seen in historical control data. There were no compound-related changes in body weights of pups. No abnormal findings considered to be attributable to administration of this compound were observed in dead pups during lactation and pups at scheduled sacrifice. Based on these findings,the NOAEL of disodium succinate hexahydrate for reproduction/developmental toxicity was considered to be 1,000 mg/kg bw/day in rats (highest dose tested) (1,000 mg of disodium succinate hexahydrate is equivalent to 600 mg of disodium succinate).

Studies in Humans

There is no available information on humans.

Conclusion

In an OECD combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, there was no evidence of reproduction/developmental toxicity in rats. The NOAEL for reproduction/developmental toxicity was considered to be 1,000 mg/kg bw/day in rats (1,000 mg of disodium succinate hexahydrate is equivalent to 600 mg of disodium succinate ).

3.1.7 Other human health related information

There is no available information. 

3.1.8 Information on structurally related chemicals

Succinic acid (CAS No.: 110-15-6)

Succinic acid is a natural constituent of plants and animals. This chemical is involved in the citric acid cycle [NTIS, 1975]. The Oral LD50 value in rats was reported to be 2,260 mg/kg bw [KODAK, Company Reports]. This chemical was not mutagenic in the Ames test and a chromosomal aberration test [Ishidate et al., 1984]. Subcutaneous injections of this compound at 31 mg/kg bw/day for three weeks did not change the typical diestrous vaginal smears in two months old ovariectomized rats [Dye et al., 1944]. Application of this compound at 750 g produced severe damage in the rabbit eyes [AJOPAA, 1946].

Monosodium succinate (CAS No.: 2922-54-5)

The oral LD50 value was greater than 8,000 mg/kg bw in rats [Maekawa et al: 1990]. In a 13-week oral toxicity study in rats, the only suppression of body weight gain was found at greater than 2.5% in the drinking water [Maekawa et al: 1990]. In a 2-year toxicity/carcinogenicity study in rats, this chemical had neither toxic nor carcinogenic activity when it was given continuously at levels of 1or 2% in drinking water [Maekawa et al: 1990].

3.2 Initial Assessment for Human Health

There is no available information on toxicokinetics and metabolism.

The oral acute toxicity study [OECD TG 401] of disodium succinate hexahydrate showed that this chemical did not cause any changes even at 2,000 mg/kg. The oral LD50 value was considered to be greater than 2,000 mg/kg bw in male and female rats (2,000 mg of disodium succinate hexahydrate is equivalent to 1,200 mg of disodium succinate ). There is no available information on the eye and skin irritation and sensitization.

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [OECD TG 422], Crj: CD (SD) IGS rats were given disodium succinate hexahydrate by gavage at 0, 100, 300, or 1,000 mg/kg bw/day. Males were dosed for 52 days from day 14 before mating and females were dosed from day 14 before mating to day 4 of lactation throughout the mating and pregnancy period. Slight loose stool was observed in four of the 12 males at 1,000 mg/kg bw/day.

No compound-related changes in the body weight, food consumption, hematology, blood coagulation, or histopathological findings were found. The blood urea nitrogen levels were

increased in females at 1,000 mg/kg bw/day. Higher levels (300mg/dL and higher) of urinary protein were found in one and two of the five males at 300 and 1,000 mg/kg bw/day, respectively,whereas no animals with these high levels were found in the control and 100 mg/kg bw/day groups.

These findings suggest the adverse effects of this compound on the kidney. Therefore, the NOAEL of disodium succinate hexahydrate for repeated dose toxicity was considered to be 100 mg/kg bw/day for male rats and 300 mg/kg bw/day for female rats (100 and 300 mg of disodium succinate hexahydrate are equivalent to 60 and 180 mg of disodium succinate, respectively).

In a reverse gene mutation assay [OECD TG 471], disodium succinate hexahydrate was not mutagenic in Salmonella typhimurium TA98, TA100, TA1535, and TA1537, and Escherichia coli

WP2 uvrA with and without an exogenous metabolic activation. In a chromosomal aberration test [OECD TG 473], disodium succinate hexahydrate did not induce structural chromosomal

aberrations or polyploidy with and without an exogenous metabolic activation in cultured Chinese hamster lung (CHL/IU) cells.

There is no data available on the carcinogenicity. 

The above-mentioned combined study [OECD TG 422] showed the reproduction/developmental parameters, i.e., mating, pregnancy, delivery, lactation, and viability and body weight of pups, were not affected by administration of disodium succinate hexahydrate at up to 1,000 mg/kg bw/day.

The NOAEL of disodium succinate hexahydrate for reproduction/developmental toxicity was considered to be 1,000 mg/kg bw/day in rats (1,000 mg of disodium succinate hexahydrate is equivalent to 600 mg of disodium succinate). 

4 HAZARDS TO THE ENVIRONMENT

4.1 Aquatic Effects

Acute Toxicity Test Results

The toxicity of disodium succinate on aquatic organisms has been studied in three freshwater species belonging to three trophic levels as shown in Table 4. These tests were conducted using disodium succinate hexahydrate (CAS No.: 6106-21-4) instead of the test substance, because disodium succinate is stable as hexahydrate, available commercially, and there should be no difference regarding environmental behavior and aquatic toxicity.

Therefore concentrations are represented as disodium succinate (anhydrate). 

In an algal growth inhibition test (OECD TG 201, open system), the acute toxicity results (72 h ErC50 and 72 h EbC50) to Selenastrum capricornutum were were determined to be >998 mg/L by both the biomass method and the growth rate method. In addition, toxicity to four marine algal species, (Navicula) sp, Chaetoceros gracilis, Pavlova lutheri and Tetraselmis tetrathele, was reported by OHGAI et al. (1993). Growth inhibition (on growth rate for seven days) was observed at the concentration of 300 mg/L of disodium succinate, however the pH was extremely decreased (pH = 3.8) in the test solutions at 300 mg/L. The details regarding this test were not available, and its reliability could not be determined. 

Regarding acute toxicity to daphnids, a 48 h EC0 of 997 mg/L and a 48 h EC50 > 997 mg/L were reported (OECD TG 202, Daphnia magna, static).

A test with fish (OECD TG 203, Oryzias latipes, flow-through) resulted in a 96 h LC0 of 47.0 mg/L, 96 h LC50 > 95.4 mg/L and 96 h LC100 > 95.4 mg/L. In this test, only one individual out of twenty died at the highest concentration of 95.4 mg/L.

All acute toxicity tests (except that using marine species) were conducted in compliance with GLP and the results were estimated based on the mean measured concentrations.

Chronic Toxicity Test Results Regarding chronic toxicity to algae, a 72 h NOErC of 998 mg/L and a NOEbC of 998 mg/L (OECD TG 201, Selenastrum capricornutum, open system) were reported. In daphnids, the effect of disodium succinate on reproduction of Daphnia magna (OECD TG 211, semi-static) was investigated. The 21 d EC50 was more than 95.2 mg/L and a 21 d NOEC of 95.2 mg/L were reported (MOE Japan, 2001). For mortality of parent daphnids, the 21 d LC50 was more than 95.2 mg/L. In these toxicity tests, no adverse effects of the chemical on reproduction of daphnids and/or growth of algae were observed at the highest concentrations.

4.2 Terrestrial Effects

There is no available information.

4.3 Initial Assessment for the Environment

Disodium succinate is a white powder with a melting point of more than 400 degree C, a water solubility of more than 100 g/L. This chemical is stable at pH 4, 7 and 9 at 50 degree C for 5 days,and readily biodegradable. A vapour pressure of 1.16x10-5 Pa is calculated. A Log Pow of < -0.59 is estimated and the bioaccumulation potential of disodium succinate is expected to be low.

The toxicity of disodium succinate on aquatic organisms has been studied in three freshwater species belonging to three trophic levels. The toxicity tests were conducted using disodium succinate hexahydrate instead of the test substance because disodium succinate hexahydrate is not different to the test substance in aqueous solution and disodium succinate is stable as hexahydrate.

In an algal growth inhibition test (OECD TG 201, Selenastrum capricornutum, open system), the 72 h ErC50 and the 72 h EbC50 were >998 mg/L. For daphnids, a 48 h EC0 of 997 mg/L and a 48 h EC50 > 997 mg/L were reported (OECD TG 202, Daphnia magna, static). For fish (OECD TG 203, Oryzias latipes, flow-through) a 96 h LC0 of 47.0 mg/L, 96 h LC50 >95.4 mg/L and 96 h LC100 > 95.4 mg/L were determined.

Regarding chronic toxicity to algae, a 72 h NOErC of 998 mg/L and a NOEbC 998 mg/L (OECD TG 201, Selenastrum capricornutum, open system) were reported. For daphnids, the 21 d EC50 was more than 95.2 mg and a 21 d NOEC of 95.2 mg/L on reproduction and a 21 d LC50 > 95.2 mg/L for parent daphnids were reported (OECD TG 211, Daphnia magna, semi-static).

There is no information available on toxicity to terrestrial or other organisms. 

5 RECOMMENDATIONS

The chemical is currently of low priority for further work based on a low hazard potential. 

OECD SIDS DISODIUM SUCCINATE UNEP PUBLICATIONS 17

6 REFERENCES

AJOPAA (1946) Am. J. Ophthamol., 29, 1363.

Chemicals Evaluation and Research Institute (CERI), Japan (2000) Unpublished data. Report

number K-1110.

Dye, WS. et al. (1944) Growth, 8, 1-11.

Fujita, H. et al. (1994) Ann. Rep. Tokyo Metr. Res. Lab. P.H., 45, 191-199.

Hansh, C. et al. (1995) SRC PHYS PROP DATA BASE.

Ishidate, M. et al. (1984) Fd Chem. Toxicol., 22, 623-636.

Maekawa, A. et al. (1990) Fd Chem. Toxicol., 28, 235-241.

MHLW (Ministry of Health, Labor and Welfare), Japan (2002) Toxicity Testing Reports of

Environmental Chemicals, 9, 383-411.

MOE (Ministry of the Environment) Japan (2001) Unpublished data.

NITS (1975) National Technical Information Service PB254541.

Ohgai, M. et al. (1993) Nippon Suisan Gakkaisi, 59, 647-652. 

Methylprednisolone Disodium succinate Injection

MethylPREDNISolone Disodium succinate for Injection, USP

Rx only

The formulations containing benzyl alcohol should not be used in neonates.

For Intravenous or Intramuscular Administration

Methylprednisolone Disodium succinate Injection Description

Methylprednisolone Disodium succinate for injection, USP is an anti-inflammatory glucocorticoid, which contains methylprednisolone Disodium succinate as the active ingredient. Methylprednisolone Disodium succinate USP, is the Disodium succinate ester of methylprednisolone, and it occurs as a white, or nearly white, odorless hygroscopic, amorphous solid. It is very soluble in water and in alcohol; it is insoluble in chloroform and is very slightly soluble in acetone.

Methylprednisolone Disodium succinate USP is the sodium salt of Methylprednisolone hemisuccinate USP, which is formed in situ, with the aid of sodium hydroxide.

The chemical name for methylprednisolone Disodium succinate is pregna-1,4-diene-3,20-dione,21-(3-carboxy-1-oxopropoxy)-11,17-dihydroxy-6-methyl-monosodium salt, (6, 11), and the molecular weight is 496.53. The structural formula is represented below:

Methylprednisolone Disodium succinate USP is soluble in water; it may be administered in a small volume of diluent and is well suited for intravenous use in situations where high blood levels of methylprednisolone are required rapidly.

Methylprednisolone Disodium succinate for injection, USP is a sterile, white color lyophilized cake, available in preservative and preservative-free formulations:

40 mg (Single Dose Vial):

Each mL (when mixed with 1 mL of Water for Injection USP) contains 53 mg of methylprednisolone Disodium succinate USP equivalent to 40 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; 17.46 mg dibasic sodium phosphate dried; 25 mg lactose hydrous. This package does not contain diluent.

Each mL (when mixed with 1 mL of Bacteriostatic Water for Injection USP) contains 53 mg of methylprednisolone Disodium succinate USP equivalent to 40 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; 17.46 mg dibasic sodium phosphate dried; 25 mg lactose hydrous. This package does not contain diluent. Recommended diluent (Bacteriostatic water) contains benzyl alcohol as a preservative.

125 mg (Single Dose Vial):

Each 2 mL (when mixed with 2 mL of Water for Injection USP) contains 165.74 mg of methylprednisolone Disodium succinate USP equivalent to 125 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; 17.4 mg dibasic sodium phosphate dried. This package does not contain diluent.

Each 2 mL (when mixed with 2 mL of Bacteriostatic Water for Injection USP) contains 165.74 mg of methylprednisolone Disodium succinate USP equivalent to 125 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; 17.4 mg dibasic sodium phosphate dried. This package does not contain diluent. Recommended diluent (Bacteriostatic water) contains benzyl alcohol as a preservative.

500 mg (Multiple Dose Vial):

Each 8 mL (when mixed with 8 mL of Bacteriostatic Water for Injection USP) contains 663 mg of methylprednisolone Disodium succinate USP equivalent to 500 mg methylprednisolone; also 6.4 mg monobasic sodium phosphate anhydrous; 69.6 mg dibasic sodium phosphate dried. This package does not contain diluent. Recommended diluent (Bacteriostatic water) contains benzyl alcohol as a preservative.

2 grams (Single Dose Vial):

Each 30.6 mL (when mixed with 30 mL of Bacteriostatic Water for Injection USP) contains 2.65 grams of methylprednisolone Disodium succinate USP equivalent to 2 grams methylprednisolone; also 25.6 mg monobasic sodium phosphate anhydrous; 278 mg dibasic sodium phosphate dried. This package does not contain diluent. Recommended diluent (Bacteriostatic water) contains benzyl alcohol as a preservative.

IMPORTANT Use only Water for Injection or Bacteriostatic Water for Injection with Benzyl Alcohol as described above when reconstituting methylprednisolone Disodium succinate for injection, USP. Use within 48 hours after mixing.

When necessary, the pH of each formula was adjusted with sodium hydroxide so that the pH of the reconstituted solution is within the USP specified range of 7 to 8 and the tonicities are, for the 40 mg per mL solution, 0.50 osmolar; for the 125 mg per 2 mL solution, 0.40 osmolar; for the 2 gram per 30.6 mL solutions, 0.42 osmolar. (Isotonic saline = 0.28 osmolar.)

Methylprednisolone Disodium succinate Injection - Clinical Pharmacology

Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract.

Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of many organ systems.

Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the bodys immune responses to diverse stimuli.

Methylprednisolone is a potent anti-inflammatory steroid with greater anti-inflammatory potency than prednisolone and even less tendency than prednisolone to induce sodium and water retention.

Methylprednisolone Disodium succinate has the same metabolic and anti-inflammatory actions as methylprednisolone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. Following the intravenous injection of methylprednisolone Disodium succinate, demonstrable effects are evident within one hour and persist for a variable period. Excretion of the administered dose is nearly complete within 12 hours. Thus, if constantly high blood levels are required, injections should be made every 4 to 6 hours. This preparation is also rapidly absorbed when administered intramuscularly and is excreted in a pattern similar to that observed after intravenous injection.

Indications and Usage for Methylprednisolone Disodium succinate Injection

When oral therapy is not feasible, and the strength, dosage form, and route of administration of the drug reasonably lend the preparation to the treatment of the condition, the intravenous or intramuscular use of methylprednisolone Disodium succinate for injection, 

Contraindications

Methylprednisolone Disodium succinate for injection is contraindicated:

in systemic fungal infections and patients with known hypersensitivity to the product and its constituents.

for intrathecal administration. Reports of severe medical events have been associated with this route of administration.

Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura.

Additional contraindication for the use of methylprednisolone Disodium succinate for injection preserved with benzyl alcohol:


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