NAPHTHALENE SULFONATE

NAPHTHALENE SULFONATE

CAS No. : 130-14-3
EC No. : 204-976-0

Synonyms:
amaranth dye; amido black; congo red; suramin; trypan blue; naftalin sülfonat; powercon 100; powercon100; Naphthalenesulfonate; NS; SNS; Naphthalenesulphonate; Naphthalene sulfonate; Naphthalene sulphonate; sulfonate naphthalene; spolostan; 2-Naphthalenesulfonic acid sodium salt; Sodium 1-naphthalenesulfonate; 130-14-3; sodium naphthalene-1-sulfonate; 1-Naphthalenesulfonic acid sodium salt; Sodium naphthalenesulphonate; Sodium naphthalene sulfonate; 1-Naphthalenesulfonic acid, sodium salt; UNII-MAI7V3C3PN; 1-Naphthalenesulfonic acid, sodium salt (1:1); alpha salt; Sodium alpha-naphthalenesulfonate; 1321-69-3; Naphthalene-1-sulphonic acid sodium salt; Sodium naphthalene-1-sulphonate; Sodium alpha-naphthylsulfonate; EINECS 204-976-0; Sodium alpha-naphthalenesulfonic acid; naphthaline-1-sulfonic acid; Sodiumnaphthalene-1-sulfonate; SODIUM 1-NAPHTHALENESULFONATE; Sodium naphthalene-1-sulphonate; Sodium1-Naphthalenesulfonate> 1-Naphthalene Sulphonic acid (Na); 1-NAPTHALENE SULFONIC ACID SODIUM SALT; 1-NAPHTHALENESULFONIC ACID SODIUM SALT; NAPHTHALENE-1-SULFONIC ACID SODIUM SALT; 1-NAPHTHALENE SULPHONIC ACID SODIUM SALT; NSC 37036; Sodium |A-naphthalene; alpha-Naphthalenesulfonic acid sodium salt; ACMC-209bhj; sodium naphthalenesulfonate; sodium naphthalene sulphonate; Naphthalene sulfonic acid, sodium salt solution (40% or less); EINECS 215-323-4; Sodium naphthalene sulfonate solution; Naphthalenesulfonic acid, sodium salt; NAPHTHALENE SULFONATE; 1-Naphthalene Sulfonic Acid, Monosodium salt; FT-0631758; N0015; Naphthalene sulfonic acid, sodium salt solution; Sodium 1-naphthalenesulfonate, >=90% (HPLC); Q-200128; Sodium 1-naphthalenesulfonate, technical grade, 80%; Sodium naphthalene sulfonate solution (40% or less); naphthalene-1-sulfonate; 1-naphthalenesulfonate; alpha-naphthalenesulfonate; naphthalene-1-sulfonate(1-); naphthalenesulfonate; naphthalene sulfonate; naphthalene; 91-20-3; Naphthalin; Naphthene; Camphor tar; Tar camphor; White tar; Albocarbon; Naphthaline; Moth flakes; Moth balls; naphtalene; Dezodorator; Naftalen; Mighty 150; napthalene; RCRA waste number U165; Mighty RD1; naftaleno; Mothballs; Naftalen [Polish]; Caswell No. 587; naftalina; naphtaline; naphthalen; Naphthalene [BSI:ISO]; Naphtalene [ISO:French]; Naphthalene, pure; NSC 37565; Naphthalene, molten; Naphthalene, 99%; EPA Pesticide Chemical Code 055801; Naphthalene, crude or refined; Naphthalene, analytical standard; Naphtalinum; NAPHTHALENE SULFONATE; Naphthalinum; CAS-91-20-3; Naphthalene, 99+%, scintillation grade; 2-naphthalen; 1-Naphthalene; 2-Naphthalene; Naphthalene,(S); Naphthalene, crude; Naphthalene, 98%; Naphthalene, for synthesis, 98.5%; Naphthalene 100 microg/mL in Methanol; naftalin sülfonat; Naphthalene 10 microg/mL in Cyclohexane; Naphthalene 10 microg/mL in Acetonitrile; Naphthalene 100 microg/mL in Acetonitrile; Naphthalene, SAJ first grade, >=98.0%; amaranth dye; amido black; congo red; suramin; trypan blue; Bicyclo[4.4.0]deca-1,3,5,7,9-pentene; Naphthalene, suitable for scintillation, >=99%; Naphthalene, molten [UN2304] [Flammable solid]; Naphthalene, molten [UN2304] [Flammable solid]; Melting point standard 79-81C, analytical standard; Naphthalene, certified reference material, TraceCERT(R); Sodium 2-naphthalenesulfonate; 532-02-5; Sodium naphthalene-2-sulfonate; 2-Naphthalenesulfonic acid sodium salt; 2-Naphthalenesulfonic acid, sodium salt; Sodium naphthalene-2-sulphonate; 2-Naphthalene sulfonic acid sodium salt; UNII-R5F0CTD2OJ; Sodium-2-naphthalenesulfonate; Sodium naphthalene-6-sulfonate; Sodium beta-naphthalenesulfonate; beta-Naphthalenesulfonic sodium salt; NSC 7415; EINECS 208-523-8; R5F0CTD2OJ; Sodium salt of beta-naphthalenesulfonic acid; 2-Naphthalenesulfonic acid, sodium salt (1:1); naphthalene sulfonate solution; Naphthalenesulfonic acid, sodium salt; 1-Naphthalene Sulfonic Acid, Monosodium salt; FT-0631758; N0015; Naphthalene sulfonic acid, sodium salt solution; Sodium 1-naphthalenesulfonate

Naphthalene Sulfonate

Naphthalene sulfonates are derivatives of sulfonic acid which contain a naphthalene functional unit. A related family of compounds are the aminonaphthalenesulfonic acids. Of commercial importance are the alkylnaphthalene sulfonates, which are used as superplasticizers in concrete. They are produced on a large scale by condensation of naphthalene sulfonate or alkylnaphthalene sulfonates with formaldehyde.
Examples include:
amaranth dye; amido black; armstrong's acid; congo red; evans blue; suramin; trypan blue

Naphthalene sulfonates can be used in a variety of applications. Nease Performance Chemicals provides naphthalene sulfonates with excellent wetting and dispersing properties. The Nease portfolio naphthalene sulfonates includes products which vary in foaming tendency – from medium to low. Additionally, they offer acid and base stability, hard-water tolerance and high temperature stability.
Nease Performance Chemicals is an industry leader in high-performance naphthalene sulfonates. Several different series of naphthalene sulfonates are available to fit specific applications. Naphthalene sulfonates can be utilized in water-based cleaners such as carpet shampoos, automatic dishwashing detergents, and industrial detergents, as well as in emulsion polymerization, photographic solutions, and agricultural formulations. One grade of naphthalene sulfonate can also be used as a dispersant in many areas, which include textile chemicals, pesticide formulations, cements, emulsion polymerization, pigments and dyestuffs, and leather tanning.
We even offer an environmentally friendly product line of naphthalene sulfonates that are classified as “ultimately biodegradable” and have “low aquatic toxicity”.

For sodium 2-naphthalene sulfonate (USEPA/OPP Pesticide Code: 217202) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./
Kao Corp reported that sodium naphthalene sulfonate is made by reacting naphthalene with sulfuric acid. The resulting naphthalene sulfonic acid is then reacted with sodium hydroxide. Formaldehyde is not used in the manufacture of this ingredient.

Incremental alternating additions of sulfonating agent acids and alkylating alcohols give superior results in the synthesis of alkyl naphthalene sulfonate surfactant products from naphthalene starting material.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to improved processes for making the products commonly known in commerce as "alkyl naphthalene sulfonates", even though they also may contain unreacted naphthalene, alkyl naphthalenes, and molecules with more than one alkyl group and/or sulfonate group per naphthalene molecule. The products are commercially important surfactants, particularly for agricultural use, and are normally made by reacting naphthalene with alcohols, sulfuric acid, and oleum.

2. Statement of Related Art
Butyl naphthalene sulfonate is now commercially made by reacting naphthalene, normal butanol, concentrated sulfuric acid, and oleum in a one-step batch type process. The process normally experiences a vigorous exotherm that is difficult to control and produces large amounts of sulfur containing by-products. On the other hand, isopropyl naphthalene sulfonate is now commercially made by a two-step process, with sulfonation followed by alkylation. While easier to control than the one step process, this two-step process is notably slower and also consumes more acid for by-products than is desirable. Similar situations prevail for other alkyl naphthalene sulfonate products.
After any of these syntheses, the initially formed alkyl naphthalene sulfonic acid is usually converted to the desired surfactant by dissolution in aqueous alkali to convert the acid to a salt. The surfactant may be used directly in the aqueous solution thus formed, or the solution may be dried to produce solid surfactant.
A material known in the art as "free oil" is a common but undesirable constituent of commercial alkyl naphthalene sulfonates. This material is largely unreacted naphthalene and/or unsulfonated alkyl naphthalene(s), and it is common commercial practice to impose an upper limit on the amount of free oil that is acceptable in the product. Another common and undesirable constituent of commercial alkyl naphthalene sulfonates is sulfate salts, formed during neutralization from residual sulfuric acid in the initial reaction product. Limiting the amounts of both these constituents is therefore a desirable goal of any process for making alkyl naphthalene sulfonate surfactants.
It is an object of this invention to provide a process for making alkyl naphthalene sulfonates that avoids or reduces at least some of the difficulties and/or byproducts occurring with present commercial processes.

SUMMARY OF THE INVENTION
It has been found that two major changes from prior art practice greatly improve processes for making alkyl naphthalene sulfonates, particularly those with alkyl groups containing from 1 to 4 carbon atoms. One of these changes is that sulfuric acid and/or oleum and alcohols that contain the alkyl groups desired in the product are added to liquid naphthalene intermittently in small increments, at least at the beginning of the process. Each increment is not more than 10%, more preferably not more than 5%, or still more preferably not more than 2.5% of the amount of the reagent concerned that would be sufficient for complete reaction to the extent desired for the product. The second major novel feature of a process according to this invention is that at an intermediate stage in the reaction, an acid rich second liquid phase is separated from the organic rich first phase, in order to avoid wasting much of the subsequently added sulfuric acid and oleum by its dissolution in the second liquid phase, rather than sulfonating remaining unsulfonated naphthalene and/or alkyl naphthalene(s) in the other liquid phase as desired.

The preferred temperature for a process according to this invention varies somewhat with the alkylating agent used. Although an unreactive solvent could be used, it is generally strongly preferred to avoid such a solvent, and in order to have a liquid form of Naphthalene sulfonate as is strongly preferred, this requires a minimum temperature of 80° C., the melting point of Naphthalene sulfonate. The lower that the temperature can be maintained above this practical limit, the less likely is the development of undesirable colored byproducts that reduce the commercial value and/or acceptability of the eventual products. On the other hand, with some alkylating agents such as normal butanol, the reaction is too slow to be practical below about 110° C. For isopropyl alcohol and secondary butyl alcohol, two preferred alkylating agents, an operating temperature between 80 and 90, or more preferably between 83 and 87, degrees Centigrade is preferred.

The strength of the oleum to be used and the proportions of oleum and sulfuric acid to be used in a process according to this invention also may be varied within wide limits, but generally the proportion between oleum and sulfuric acid found useful in the prior art will also be useful for a process according to this invention. It is generally preferred to use enough total sulfonating agent by the end of the process to obtain an average of at least one sulfur atom per Naphthalene sulfonate nucleus in the product, but because of the equilibrium character of the sulfonation reaction, readily detectable amounts of unsulfonated Naphthalene sulfonate nuclei generally remain as part of the "free oil" component mentioned earlier. Some Naphthalene sulfonate nuclei with two or more sulfonate groups are also presumed to be present, although no exhaustive analysis of the products of a process according to this invention has been made.
The amount of alkylating agent used during the complete process also generally should preferably be sufficient to produce a product with an average of at least one alkyl group per Naphthalene sulfonate nucleus. For the alkyl groups, especially butyl, it is still more preferred to have an average of at least 1.1 or still more preferably 1.2 alkyl groups per Naphthalene sulfonate nucleus in the final product. Although it is normally preferred to use an alkylating agent that consists primarily of a single molecular type of alcohol, mixtures of alcohols work effectively in the process as well.

After the separation has been accomplished, additional amounts of sulfuric acid, oleum, or both are added to the liquid phase that contains still unsulfonated Naphthalene sulfonate nuclei. Eventually, a sufficient amount of sulfonating agent to achieve an average degree of sulfonation of at least one bonded sulfur atom per Naphthalene sulfonate nucleus and to reduce the amount of free oil in the final product to not more than 1.5% should be used. If the reaction product at the time of the separation from the second liquid phase has a lower average degree of alkylation than is desired for the final product, more alkylating agent may also be added after this phase separation. As is true during the earlier phases of reaction, it is preferable during this phase of reaction to add sulfonating agent and alkylating agent in small increments, with alternating additions of sulfonating agent and of alkylating agent as long as both such reagents are needed to achieve the desired degree of alkylation and sulfonation for the final product, and to time such additions so as to maintain a nearly constant temperature within the reaction mixture.

After the completion of the sulfonation and alkylation reactions, the liquid phase containing the products is dissolved in and/or reacted with an alkaline aqueous solution, additional alkali is added if necessary, and the final desired alkyl Naphthalene sulfonate sulfonate surfactants are recovered for use, either as aqueous solutions or in solid form after drying. These final steps are performed in the same general manner as for corresponding steps in the prior art.

In accordance with the discussion above, a process according to the invention comprises steps of:
(A) mixing a specified mass of liquid Naphthalene sulfonate with a first incremental mass of liquid acid selected from the group consisting of sulfuric acid and oleum, said first incremental mass being not more than a specified first proper fraction of the amount sufficient to sulfonate the specified mass of Naphthalene sulfonate with one sulfonate group per Naphthalene sulfonate molecule;

(B) mixing with the mixture formed in step (A) a second incremental mass of alkylating alcohols, said second incremental mass being not more than a specified second proper fraction of the amount sufficient to alkylate the specified mass of Naphthalene sulfonate with one alkyl group per Naphthalene sulfonate molecule and also being small enough that the concentration of gaseous hydrocarbon formed by dehydration of the alkylating alcohols to olefin during mixing does not exceed 100 ppm in the gas phase above the reaction mixture;

(C) mixing with the mixture formed in the previous step a third incremental mass of liquid acid selected from the group consisting of sulfuric acid and oleum, said third incremental mass being not more than a specified third proper fraction of the amount sufficient to sulfonate the specified mass of Naphthalene sulfonate with one sulfonate group per Naphthalene sulfonate molecule;

(D) mixing with the mixture formed in the previous step a fourth incremental mass of alkylating alcohols, said fourth incremental mass being not more than a specified fourth proper fraction of the amount sufficient to alkylate the specified mass of Naphthalene sulfonate with one alkyl group per Naphthalene sulfonate molecule and also being small enough that the concentration of gaseous hydrocarbon formed by dehydration of the alkylating alcohols to olefin during the mixing does not exceed 100 ppm in the gas phase over the reaction mixture;

(E) repeating steps (C) and (D) sufficiently many times that when mixing is discontinued after the last repetition of step (D), the resulting liquid mixture spontaneously separates into two liquid phases, the second, denser, aqueous one of said phases being more concentrated in sulfuric acid than the other phase and the other, first, organic one of said phases being more concentrated in total organic materials than the aqueous second phase; the total amount of liquid acid used in all of steps (A)-(D) and all repetitions of steps (C) and (D) being less than the amount required to sulfonate the specified mass of Naphthalene sulfonate with at least one sulfonate group per Naphthalene sulfonate molecule;

(F) separating the organic phase recited in part (E) from the aqueous phase recited therein;
(G) mixing with the organic phase separated in part (E) a fifth incremental mass of liquid acid selected from the group consisting of sulfuric acid and oleum, said fifth incremental mass being not more than a specified fifth proper fraction of the amount sufficient to sulfonate the specified mass of Naphthalene sulfonate with at least one sulfonate group per Naphthalene sulfonate molecule;
(H) if the total amount of alkylating alcohols mixed with the specified mass of Naphthalene sulfonate by the completion of the previous step is not sufficient to alkylate all the specified mass of Naphthalene sulfonate with at least one alkyl group per molecule of Naphthalene sulfonate, mixing with the mixture formed in the previous step a sixth incremental mass of alkylating alcohols, said sixth incremental mass being not more than a specified sixth proper fraction of the amount sufficient to alkylate the specified mass of Naphthalene sulfonate with one alkyl group per Naphthalene sulfonate molecule and also being small enough that the concentration of gaseous hydrocarbon formed by dehydration of the alkylating alcohols to olefin during the mixing does not exceed 100 ppm in the gas phase over the reaction mixture

While the invention is not to be regarded as limited by any theory, it is believed that the superior results obtained by alternating incremental additions of the sulfonating and alkylating agents may perhaps be explicable as follows: The least desirable organic ingredients in the product mixture are those with either no sulfonate groups or no alkyl groups on individual Naphthalene sulfonate molecules. When large amounts of sulfonating agents are added initially, most of the Naphthalene sulfonate nuclei become sulfonated, thereby reducing the reactivity for subsequent alkylation by the well known deactivating effect of sulfonate substituents on aromatic rings. Higher temperatures must then be used to achieve a practical reaction rate, increasing the danger of byproducts. On the other hand, alcohols will not alkylate Naphthalene sulfonate at all in the absence of some acid to serve as catalyst. When a small amount of acid is used at the start, followed by a small amount of alcohol, most of the acid may be bound to the alcohol by temporary bonds that produce the catalytic electrophilic alkylating species, and thereby temporarily unavailable for sulfonating the rings. Once a particular Naphthalene sulfonate nucleus has been alkylated, it is more reactive to sulfonation than either the residual unsubstituted Naphthalene sulfonate or any sulfonated Naphthalene sulfonate that may be present. Therefore, most of the next added increment of sulfonating agent will sulfonate already alkylated Naphthalene sulfonate molecules, and the amount of undesirable product molecules with only one of the two types of substituents will be minimized.

What is claimed is:
1. A process for making surfactant material, said process comprising steps of:
(A) mixing a specified mass of liquid Naphthalene sulfonate with a first incremental mass of liquid acid selected from the group consisting of sulfuric acid and oleum, said first incremental mass being not more than a specified first proper fraction of the amount sufficient to sulfonate the specified mass of Naphthalene sulfonate with one sulfonate group per Naphthalene sulfonate molecule;
(B) mixing with the mixture formed in step (A) a second incremental mass of alkylating alcohols, said second incremental mass being not more than a specified second proper fraction of the amount sufficient to alkylate the specified mass of Naphthalene sulfonate with one alkyl group per Naphthalene sulfonate molecule and also being small enough that the concentration of gaseous hydrocarbon formed by dehydration of the alkylating alcohols to olefin during mixing does not exceed about 100 ppm in the gas phase above the reaction mixture;
(C) mixing with the mixture formed in the previous step a third incremental mass of liquid acid selected from the group consisting of sulfuric acid and oleum, said third incremental mass being not more than a specified third proper fraction of the amount sufficient to sulfonate the specified mass of Naphthalene sulfonate with one sulfonate group per Naphthalene sulfonate molecule;

(D) mixing with the mixture formed in the previous step a fourth incremental mass of alkylating alcohols, said fourth incremental mass being not more than a specified fourth proper fraction of the amount sufficient to alkylate the specified mass of Naphthalene sulfonate with one alkyl group per Naphthalene sulfonate molecule and also being small enough that the concentration of gaseous hydrocarbon formed by dehydration of the alkylating alcohols to olefin during the mixing does not exceed about 100 ppm in the gas phase over the reaction mixture;
(E) repeating steps (C) and (D) sufficiently many times that when mixing is discontinued after the last repetition of step (D), the resulting liquid mixture spontaneously separates into two liquid phases, the second, denser, aqueous one of said phases being more concentrated in sulfuric acid than the other phase and the other, first, organic one of said phases being more concentrated in total organic materials than the aqueous second phase; the total amount of liquid acid used in all of steps (A)-(D) and all repetitions of steps (C) and (D) being less than the amount required to sulfonate the specified mass of Naphthalene sulfonate with at least one sulfonate group per Naphthalene sulfonate molecule;
(F) separating the organic phase recited in part (E) from the aqueous phase recited therein;
(G) mixing with the organic phase separated in part (E) a fifth incremental mass of liquid acid selected from the group consisting of sulfuric acid and oleum, said fifth incremental mass being not more than a specified fifth proper fraction of the amount sufficient to sulfonate the specified mass of Naphthalene sulfonate with at least one sulfonate group per Naphthalene sulfonate molecule;

(H) if the total amount of alkylating alcohols mixed with the specified mass of Naphthalene sulfonate by the completion of the previous step is not sufficient to alkylate all the specified mass of Naphthalene sulfonate with at least one alkyl group per molecule of Naphthalene sulfonate, mixing with the mixture formed in the previous step a sixth incremental mass of alkylating alcohols, said sixth incremental mass being not more than a specified sixth proper fraction of the amount sufficient to alkylate the specified mass of Naphthalene sulfonate with one alkyl group per Naphthalene sulfonate molecule and also being small enough that the concentration of gaseous hydrocarbon formed by dehydration of the alkylating alcohols to olefin during the mixing does not exceed about 100 ppm in the gas phase over the reaction mixture;
(I) discontinuing agitation of the reaction mixture, so that the mixture can separate into two or more liquid phases if its contents would exist in the form of two or more liquid phases at equilibrium, and separating the resulting liquid phase that is most concentrated in organic material from the other liquid phases present if any; and
(J) dissolving the liquid phase that is most concentrated in organic material from step (I) in water and neutralizing the resulting solution with a strong alkali.

Naphthalene sulfonate is a white, volatile, solid polycyclic hydrocarbon with a strong mothball odor. Naphthalene sulfonate is obtained from either coal tar or petroleum distillation and is primarily used to manufacture phthalic anhydride, but is also used in moth repellents. Exposure to Naphthalene sulfonate is associated with hemolytic anemia, damage to the liver and neurological system, cataracts and retinal hemorrhage. Naphthalene sulfonate is reasonably anticipated to be a human carcinogen and may be associated with an increased risk of developing laryngeal and colorectal cancer.
In small oysters transport of Naphthalene sulfonate between tissues is primarily by diffusion. In intact oysters, accumulation in adductor muscle and body followed accumulation in gills after a large lag-time. In isolated tissues with no shell to impede water, there was no time lag.
It was shown/ that 24-35% of an intraperitoneal dose of (14)C-Naphthalene sulfonate was eliminated as mercapturates by both mice and rats at 24 hours after dosing. For both species, this percentage was the same over a wide dose range (3.12-200 mg/kg body weight). In contrast, after inhalation exposure, the amounts of mercapturic acid in mouse urine were approximately twice those in rat urine at the same level of exposure. Over a 24 hour period, approximately 100-500 umol/kg body weight mercapturates were eliminated in urine of mice given intraperitoneal injections of 50-200 mg/kg body weight Naphthalene sulfonate. In mice exposed by inhalation to 1-100 ppm (5.24-524 mg/cu m) Naphthalene sulfonate for 4 hours, 1-240 umol/kg body weight total mercapturic acids were eliminated, while rats exposed to the same concentrations eliminated 0.6-67 umol/kg body weight.

Naphthalene sulfonate-1,2-oxide (NPO), 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ) are the major metabolites of Naphthalene sulfonate that are thought to be responsible for the cytotoxicity and genotoxicity of this chemical. We measured cysteinyl adducts of these metabolites in hemoglobin (Hb) and albumin (Alb) from F344 rats dosed with 100-800 mg Naphthalene sulfonate/kg bw. The method employs cleavage and derivatization of these adducts by trifluoroacetic anhydride and methanesulfonic acid followed by gas chromatography-mass spectrometry in negative ion chemical ionization mode. Cysteinyl adducts of both proteins with NPO, and 1,2- and 1,4-NPQ (designated NPO-Hb and -Alb, 1,2-NPQ-Hb and -Alb, and 1,4-NPQ-Hb and -Alb, respectively) were produced in a dose-dependent manner. Of the two structural isomers resulting from NPO, levels of NPO1 adducts were greater than those of NPO2 adducts in both Hb and Alb, indicating that aromatic substitution is favored in vivo at positions 1 over 2. Of the quinone adducts, 1,2-NPQ-Hb and -Alb were produced in greater quantities than 1,4-NPQ-Hb and -Alb, indicating either that the formation of 1,2-NPQ from NPO is favored or that more than one pathway leads to the formation of 1,2-NPQ. The shapes of the dose-response curves were generally nonlinear at doses above 200 mg Naphthalene sulfonate/kg bw. However, the nature of nonlinearity differed, showing evidence of supralinearity for NPO-Hb, NPQ-Hb and NPQ-Alb and of sublinearity for NPO-Alb. Low background levels of 1,2-NPQ-Hb and -Alb and 1,4-NPQ-Hb and -Alb were detected in control animals without known exposure to Naphthalene sulfonate. However, the corresponding NPO-Hb and -Alb adducts were not detected in control animals.

Naphthalene sulfonate is first metabolized by hepatic mixed function oxidases to the epoxide, Naphthalene sulfonate-1,2-oxide. The epoxide can be enzymatically converted into the dihydrodiol, 1,2-dihydroxy-1,2-dihydroNaphthalene sulfonate or conjugated with glutathione. The dihydrodiol can then be conjugated to form a polar compound with glucuronic acid or sulfate or be further dehydrogenated to form the highly reactive 1,2-dihydroxyNaphthalene sulfonate. This too can be enzymatically conjugated with sulfate or glucuronic acid or spontaneously oxidized to form 1,2-naphthoquinone.

Naphthalene sulfonate and 2-methylNaphthalene sulfonate cause a highly organ and species selective lesion of the pulmonary bronchiolar epithelium in mice. Naphthalene sulfonate but not 2-methylNaphthalene sulfonate induced pulmonary bronchiolar injury is blocked by prior administration of the cytochrome p450 monooxygenase inhibitor piperonyl butoxide, thus suggesting that metabolism by enzyme other than the p450 monooxygenases may be important in 2-methylNaphthalene sulfonate induced injury. Since many of the polycyclic aromatic hydrocarbons are metabolized by the prostaglandin endoperoxide synthetase system and because detectable xenobiotic metabolizing activity has been associated with the prostaglandin synthetases in the Clara cell, the studies reported here were done to compare reduced nicotinamide adenine dinucleotide phosphate versus arachidonate dependent metabolism of Naphthalene sulfonate in vitro and to determine whether indomethacin, a potent inhibitor of prostaglandin biosythesis, was capable of blocking the in vivo toxicity of these two aromatic hydrocarbons. The NADPH-dependent metabolism of Naphthalene sulfonate and 2-methylNaphthalene sulfonate to covalently bound metabolites in lung or liver microsomal incubations occurred at easily measurable rates. Renal microsomal NADPH-dependent metabolism of either substrate was not detected. The formation of covalently bound Naphthalene sulfonate or 2-methylNaphthalene sulfonate metabolites was dependent upon NADPH and was inhibited by the addition of reduced glutathione, piperonyl butoxide, and SKF-525A. Covalent binding of radioactivity from (14)C 2-methylNaphthalene sulfonate also was strongly inhibited by incubation in a nitrogen atmosphere . ... The arachidonic acid-dependent formation of reactive metabolites from Naphthalene sulfonate or 2-methylNaphthalene sulfonate was undetectable in microsomal incubations from lung, liver or kidney. Indomethacin, 1 hr before and 6 hr after the administration of 300 mg/kg Naphthalene sulfonate or 2-methylNaphthalene sulfonate, failed to block the pulmonary bronchiolar injury induced by these organs. These studies suggest that the major enzymes involved in the metabolic activation of Naphthalene sulfonate or 2-methylNaphthalene sulfonate in vitro are cytochrome p450 monooxygenases and that cooxidative metabolism by the prostaglandin synthetases appears to play little role in the formation of reactive metabolites in vitro.

In an experimental animal study, doses of Naphthalene sulfonate ranging from 1 ug to 1 g were administered in the feed to 3 young pigs and their urine was collected in 2 sequential 24 hr specimens. The major urinary metabolite, conjugated 1-naphthol, was separated by gas chromatography and detected by electron capture. Most 1-naphthol excretion occurred during the first 24 hr period following dosing. Metabolic 1-naphthol could be detected after administration of as little as 100 ug Naphthalene sulfonate. A linear relationship was observed between urinary 1-naphthol and oral dose (both expressed on the log scale) in 24 hr specimen (r squared = 0.961, p<0.05) and 48 hr specimens (r squared = 0.906, p<0.05).
Following the ip administration of Naphthalene sulfonate (200 mg/kg) to mice, the lung, in comparison with other organs, was selectively damaged. Histological examination of the lung showed that it was the non-ciliated, bronchiolar epithelial cells (Clara cells) which were damaged. At higher doses (400 mg/kg and 600 mg/kg, ip), there was also damage to the cells in the proximal tubules of the kidney. In contrast to the effect in mice, doses of Naphthalene sulfonate as high as 1600 mg/kg ip caused no detectable pulmonary or renal damage in the rat. This difference in toxicity between the mouse and rat was reflected by the ability of Naphthalene sulfonate to more severely deplete the non-protein sulfhydryls in the mouse lung and kidney than in the rat. In order to investigate the species difference in toxicity, the metabolism of Naphthalene sulfonate by lung and liver microsomes of the mouse and rat was studied. In all cases, Naphthalene sulfonate was metabolized to a covalently bound product(s) and to two major methanol soluble products, which co-chromatographed with 1-naphthol and 1,2-dihydro-1,2-dihydroxyNaphthalene sulfonate. However, both the covalent binding and metabolism were approximately 10-fold greater in microsomes prepared from mouse lung compared with those from the rat.

Oral median lethal doses Naphthalene sulfonate ranged from around 350 mg/kg in mice to 2200 mg/kg in rats. The toxicity of Naphthalene sulfonate and 2-methylNaphthalene sulfonate is due to a bronchiolar necrosis that develops rapidly after inhalation exposure. Clara cells in the bronchiolar epithelium are the primary target for low doses of Naphthalene sulfonate and 2-methylNaphthalene sulfonate. When given in multiple doses to mice the bronchiolar epithelium appears to develop a tolerance to Naphthalene sulfonate. 2-MethylNaphthalene sulfonate is less acutely toxic than Naphthalene sulfonate. Mice have tolerated intraperitoneal doses of 2-methylNaphthalene sulfonate as high as 800 mg/kg. Both Naphthalene sulfonate and 2-methylNaphthalene sulfonate must be metabolically activated to form enantiomeric epoxides and diol epoxides to express their toxicity. Stereochemical investigations in the case of Naphthalene sulfonate conducted in mice have shown that a major reason for the selective injury to the bronchiolar epithelium may be the high degree to which it is epoxidated. No specific Naphthalene sulfonate or 2-methylNaphthalene sulfonate metabolite that can damage Clara cells has been identified nor has a close relationship between the metabolic binding and toxicity been established. The Clara cell toxicity of Naphthalene sulfonate and 2-methylNaphthalene sulfonate may be due to circulating

The fate of glutathione conjugates derived from Naphthalene sulfonate metabolism at various dose levels (5-80 mg/kg) were examined in an effort to explore the potential use of urinary mercapturic acids as biomarkers of exposure to Naphthalene sulfonate and as indicators of the activity and stereoselectivity of cytochrome p450 dependent Naphthalene sulfonate epoxidation. This approach extends previous studies which demonstrated a high degree of stereoselectivity in the formation of (+)-1R,2S-Naphthalene sulfonate oxide from Naphthalene sulfonate in target tissue microsomes (mouse lung), but not in microsomal preparations isolated from nontarget tissues such as mouse liver. To validate the use of mercapturic acids as indicators of epoxide formation in vivo, individual Naphthalene sulfonate oxide glutathione adduct isomers were administered iv to mice, and urinary metabolites were identified and quantified. Mercapturates accounted for 69-75% of the administered dose in the 8 hr urines of animals treated with trans-1-(S)-hydroxy-2-(S)-glutathionyl-1,2-dihydroNaphthalene sulfonate (adduct 1) and 76-84% for trans-1-(R)-hydroxy-2-(R)-glutathionyl-1,2-dihydroNaphthalene sulfonate (adduct 2). Only 39-57% of the dose of trans-1-(R)-glutathionyl-2-(R)-hydroxy-1,2-dihydroNaphthalene sulfonate (adduct 3) administered to mice was excreted as the mercapturic acid derivative; however, two additional metabolites were detected which were not present in the urine of animals treated with adducts 1 or 2. The first metabolite, accounting for 2-4% of the dose of adduct 3, was not identified. The second metabolite, isolated by HPLC and identified by mass spectrometry as (hydroxy-1,2-dihydronaphthalenylthio)pyruvic acid, accounted for 14-25% of the administered dose of adduct 3.

Naphthalene sulfonate induced pulmonary and renal toxicity and polycyclic aromatic hydrocarbon induced carcinogenesis are known to be mediated by their reactive metabolites. Subchronic exposure (90 days) of mice to Naphthalene sulfonate does not alter humoral and cellular mediated immune responses, whereas polycyclic aromatic hydrocarbons, such as benzo(a)pyrene and 7,12-dimethylbenzanthracene, are known to be immunosuppressive. To understand these differences, the antibody forming cell responses of splenocyte cultures exposed to Naphthalene sulfonate (2, 20, and 200 uM) were evaluated. At these concentrations, the antibody forming cell response to sheep red blood cells (RBC) was not affected. To determine if reactive metabolites of Naphthalene sulfonate were immunosuppressive, splenocytes were exposed to Naphthalene sulfonate metabolites by direct addition or through the use of a metabolic activation system. The addition of 1-naphthol (70 and 200 uM) and 1,4-naphthoquinone (2, 7, and 20 uM) resulted in a decreased antibody forming cell response. Suppression of antibody forming cell responses was also obtained by culturing splenocytes with liver S9 and Naphthalene sulfonate. Since splenic metabolism of Naphthalene sulfonate to nonimmunosuppressive metabolites may account for the absence of immunotoxicity, the types of Naphthalene sulfonate metabolites generated by splenic microsomes were determined. It was observed that splenic microsomes were unable to generate any detectable Naphthalene sulfonate metabolites, whereas liver microsomes were able to generate both 1,2-Naphthalene sulfonate diol and 1-naphthol. Thus, the absence of an immunosuppressive effect by Naphthalene sulfonate exposure may be related to the inability of splenocytes to metabolize Naphthalene sulfonate. Moreover, the concentration of Naphthalene sulfonate metabolites generated within the liver that may diffuse to the spleen may be inadequate to produce immunotoxicity.

The fungal metabolism of aromatic hydrocarbons has been studied using Naphthalene sulfonate and biphenyl as model compounds. Using (14)C Naphthalene sulfonate and the fungus Cunninghamella elegans, the major free metabolites were trans-1,2-dihydroxy-1,2-dihydro-Naphthalene sulfonate, 4-hydroxy-l-tetralone and 1-naphthol. The sulfate and glucuronic acid conjugates of 1-naphthol were the major water soluble metabolites which were isolated by thin layer chromatography and ion pair high pressure liquid chromatography. Field Desorption Mass Spectrometry was used to identify the sulfate conjugate whereas the trimethylsilyl derivative of the glucuronic acid conjugate was characterized by Electron Impact Mass Spectrometry. Analogous metabolites were formed from biphenyl which was hydroxylated at the 4 position and then conjugated.
The metabolism of Naphthalene sulfonate in mammals has been extensively studied. Naphthalene sulfonate is first metabolized by hepatic mixed function oxidases to the epoxide, Naphthalene sulfonate-1,2-oxide. ... The epoxide can be enzymatically converted into the dihydrodiol, 1,2-dihydroxy-1,2-dihydroNaphthalene sulfonate or conjugated with glutathione. The dihydrodiol can then be conjugated to form a polar compound with glucuronic acid or sulfate or be further dehydrogenated to form the highly reactive 1,2-dihydroxyNaphthalene sulfonate. This too can be enzymatically conjugated with sulfate or glucuronic acid or spontaneously oxidized to form another highly reactive compound, 1,2-naphthoquinone.

Naphthalene sulfonate produces species and cell selective injury to respiratory tract epithelial cells of rodents. In these studies we determined the apparent Km, Vmax, and catalytic efficiency (Vmax/Km) for Naphthalene sulfonate metabolism in microsomal preparations from subcompartments of the respiratory tract of rodents and non-human primates. In tissues with high substrate turnover, major metabolites were derived directly from Naphthalene sulfonate oxide with smaller amounts from conjugates of diol epoxide, diepoxide, and 1,2- and 1,4-naphthoquinones. In some tissues, different enzymes with dissimilar Km and Vmax appeared to metabolize Naphthalene sulfonate. The rank order of Vmax (rat olfactory epithelium>mouse olfactory epithelium>murine airways>>rat airways) correlated well with tissue susceptibility to Naphthalene sulfonate. The Vmax in monkey alveolar subcompartment was 2% that in rat nasal olfactory epithelium. Rates of metabolism in nasal compartments of the monkey were low. The catalytic efficiencies of microsomes from known susceptible tissues/subcompartments are 10 and 250 fold higher than in rat airway and monkey alveolar subcompartments, respectively. Although the strong correlations between catalytic efficiencies and tissue susceptibility suggest that non-human primate tissues are unlikely to generate metabolites at a rate sufficient to produce cellular injury, other studies showing high levels of formation of protein adducts support the need for additional studies.

 Nonciliated bronchiolar epithelial (Clara) cells of mice are highly susceptible to toxicants that undergo metabolic activation, presumably because this cell type expresses high levels of cytochrome P450 monooxygenases. To establish the capability of these cells to metabolize an agent that causes Clara cell-selective toxicity in vivo, we evaluated the metabolism of Naphthalene sulfonate in isolated cells under two distinct conditions, i.e., in homogenized cell preparations supplemented with glutathione and glutathione S-transferases and in intact cells. In homogenized cell preparations Naphthalene sulfonate was metabolized to dihydrodiol (minor) and a single glutathione adduct (major) derived from the 1R,2S-epoxide. In intact cells the rate of formation of glutathione adduct was much lower and dihydrodiol predominated. Approximately 3-10% of racemic Naphthalene sulfonate oxide added to isolated homogenized cells was converted to glutathione adducts and dihydrodiol in 3-min incubations. At high concentrations of Naphthalene sulfonate oxide (0.25 and 0.5 mM), formation of the adduct derived from the 1R,2s-epoxide was favored. The intracellular glutathione concentration, measured by high performance liquid chromatography as the fluorescence of the monobromobimane-glutathione derivative, was 1.14 +/- 0.13 nmol/10(6) cells. To determine whether Clara cell injury results from cytotoxic metabolites of Naphthalene sulfonate, we assessed viability of intact cells in response to different concentrations of Naphthalene sulfonate and Naphthalene sulfonate metabolites. At high Naphthalene sulfonate concentrations (0.5 and 1.0 mM) cell viability decreased to 63% or less of control, whereas lower concentrations (0.1 or 0.05 mM) did not alter viability significantly. Naphthalene sulfonate-induced decreases in cell viability were blocked by preincubation of Clara cells with the cytochrome P450 monooxygenase inhibitor piperonyl butoxide. The cytotoxicity of Naphthalene sulfonate metabolites varied. Incubation of cells with 0.5 mM dihydrodiol, 1-naphthol, or 1,2-naphthoquinone decreased cell viability to an extent similar to that produced by 0.5 mM Naphthalene sulfonate. In contrast, 0.5 mM Naphthalene sulfonate oxide and 1,4-naphthoquinone significantly decreased viability more than the parent compound. Preincubation of Clara cells with piperonyl butoxide did not affect the loss in cell viability associated with Naphthalene sulfonate oxide. We conclude that isolated Clara cells 1) are capable of metabolizing Naphthalene sulfonate, a Clara cell-specific cytotoxicant, to two major metabolites, 2) have a detectable intracellular glutathione pool, and 3) are more susceptible to specific Naphthalene sulfonate metabolites than to the parent compound Naphthalene sulfonate.

Naphthalene sulfonate itself is not cataractogenic; instead, the metabolite 1,2-dihydro-1,2-dihydroxyNaphthalene sulfonate (Naphthalene sulfonate dihydrodiol) is the cataract-inducing agent. Subsequent studies using biochemical and pharmacologic techniques, in vitro assays, and transgenic mice showed that aldose reductase in the rat lens is a major protein associated with Naphthalene sulfonate dihydrodiol dehydrogenase activity and that lens aldose reductase is the enzyme responsible for the formation of Naphthalene sulfonate dihydrodiol. In addition, invivo and invitro studies have shown that aldose reductase inhibitors prevent Naphthalene sulfonate-induced cataracts.
Naphthalene sulfonate has been shown to be a weak carcinogen in rats. To investigate its mechanism of metabolic activation and cancer initiation, mice were topically treated with Naphthalene sulfonate or one of its metabolites, 1-naphthol, 1,2-dihydrodiolNaphthalene sulfonate (1,2-DDN), 1,2-dihydroxyNaphthalene sulfonate (1,2-DHN), and 1,2-naphthoquinone (1,2-NQ). After 4 h, the mice were sacrificed, the treated skin was excised, and the depurinating and stable DNA adducts were analyzed. The depurinating adducts were identified and quantified by ultraperformance liquid chromatography/tandem mass spectrometry, whereas the stable adducts were quantified by (32)P-postlabeling. For comparison, the stable adducts formed when a mixture of the four deoxyribonucleoside monophosphates was treated with 1,2-NQ or enzyme-activated Naphthalene sulfonate were also analyzed. The depurinating adducts 1,2-DHN-1-N3Ade and 1,2-DHN-1-N7Gua arise from reaction of 1,2-NQ with DNA. Similarly, the major stable adducts appear to derive from the 1,2-NQ. The depurinating DNA adducts are, in general, the most abundant. Therefore, Naphthalene sulfonate undergoes metabolic activation to the electrophilic ortho-quinone, 1,2-NQ, which reacts with DNA to form depurinating adducts. This is the same mechanism as other weak carcinogens, such as the natural and synthetic estrogens, and benzene.

Naphthalene sulfonate is used in the production of phthalic anhydride; it is also used in mothballs. Acute (short- term) exposure of humans to Naphthalene sulfonate by inhalation, ingestion, and dermal contact is associated with hemolytic anemia, damage to the liver, and neurological damage. Cataracts have also been reported in workers acutely exposed to Naphthalene sulfonate by inhalation and ingestion. Chronic (long-term) exposure of workers and rodents to Naphthalene sulfonate has been reported to cause cataracts and damage to the retina. Hemolytic anemia has been reported in infants born to mothers who "sniffed" and ingested Naphthalene sulfonate (as mothballs) during pregnancy. Available data are inadequate to establish a causal relationship between exposure to Naphthalene sulfonate and cancer in humans. EPA has classified Naphthalene sulfonate as a Group C, possible human carcinogen.
If an employees' clothing becomes contaminated with solid Naphthalene sulfonate, employees should change into uncontaminated clothing before leaving the work area. Clothing contaminated with Naphthalene sulfonate should be placed into closed containers for storage until it can be discarded or until provision is made for the removal of the Naphthalene sulfonate from the clothing. If the clothing is to be laundered or cleaned to remove the Naphthalene sulfonate, the person performing the operation should be informed of Naphthalene sulfonate's hazardous properties. Non-impervious clothing which becomes contaminated with Naphthalene sulfonate should be removed promptly and not reworn until the Naphthalene sulfonate is removed from the clothing.