Residual Solvent Class | Assessment |
Class 1 | Solvents to be avoided Known human carcinogens Strongly suspected human carcinogens Environmental hazards |
Class 2 | Solvents to be limited |
Nongenotoxic animal carcinogens or possible causative agents of other irreversible toxicity, such as neurotoxicity or teratogenicity. | |
Solvents suspected of other significant but reversible toxicities. | |
Class 3 | Solvents with low toxic potential |
Solvents with low toxic potential to humans; no health-based exposure limit is needed. [noteClass 3 residual solvents have PDEs of 50 mg or more per day.]* | |
*
For residual solvents with PDEs of more than 50 mg per day, see the discussion in the section Class 3 under Limits of Residual Solvents.
|
Component | Amount in Formulation (g) |
Acetonitrile Content (ppm) |
Daily Exposure (mg) |
Drug substance | 0.3 | 800 | 0.24 |
Excipient 1 | 0.9 | 400 | 0.36 |
Excipient 2 | 3.8 | 800 | 3.04 |
Drug product | 5.0 | 728 | 3.64 |
Component | Amount in Formulation (g) |
Acetonitrile Content (ppm) |
Daily Exposure (mg) |
Drug substance | 0.3 | 800 | 0.24 |
Excipient 1 | 0.9 | 2000 | 1.80 |
Excipient 2 | 3.8 | 800 | 3.04 |
Drug product | 5.0 | 1016 | 5.08 |
Solvent | Concentration Limit (ppm) |
Concern |
Benzene | 2 | Carcinogen |
Carbon tetrachloride | 4 | Toxic and environmental hazard |
1,2-Dichloroethane | 5 | Toxic |
1,1-Dichloroethene | 8 | Toxic |
1,1,1-Trichloroethane | 1500 | Environmental hazard |
Solvent | PDE (mg/day) |
Concentration Limit (ppm) |
Acetonitrile | 4.1 | 410 |
Chlorobenzene | 3.6 | 360 |
Chloroform | 0.6 | 60 |
Cyclohexane | 38.8 | 3880 |
1,2-Dichloroethene | 18.7 | 1870 |
1,2-Dimethoxyethane | 1.0 | 100 |
N,N-Dimethylacetamide | 10.9 | 1090 |
N,N-Dimethylformamide | 8.8 | 880 |
1,4-Dioxane | 3.8 | 380 |
2-Ethoxyethanol | 1.6 | 160 |
Ethylene glycol | 6.2 | 620 |
Formamide | 2.2 | 220 |
Hexane | 2.9 | 290 |
Methanol | 30.0 | 3000 |
2-Methoxyethanol | 0.5 | 50 |
Methylbutylketone | 0.5 | 50 |
Methylcyclohexane | 11.8 | 1180 |
Methylene chloride | 6.0 | 600 |
N-Methylpyrrolidone | 5.3 | 530 |
Nitromethane | 0.5 | 50 |
Pyridine | 2.0 | 200 |
Sulfolane | 1.6 | 160 |
Tetrahydrofuran | 7.2 | 720 |
Tetralin | 1.0 | 100 |
Toluene | 8.9 | 890 |
Trichloroethylene | 0.8 | 80 |
Xylene* | 21.7 | 2170 |
*
Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene
|
Acetic acid | Heptane |
Acetone | Isobutyl acetate |
Anisole | Isopropyl acetate |
1-Butanol | Methyl acetate |
2-Butanol | 3-Methyl-1-butanol |
Butyl acetate | Methylethylketone |
tert-Butylmethyl ether | Methylisobutylketone |
Cumene | 2-Methyl-l-propanol |
Dimethyl sulfoxide | Pentane |
Ethanol | 1-Pentanol |
Ethyl acetate | 1-Propanol |
Ethyl ether | 2-Propanol |
Ethyl formate | Propyl acetate |
Formic acid |
1,1-Diethoxypropane | Methyl isopropyl ketone |
1,1-Dimethoxymethane | Methyltetrahydrofuran |
2,2-Dimethoxypropane | Solvent hexane |
Isooctane | Trichloroacetic acid |
Isopropyl ether | Trifluoroacetic acid |
Headspace Operating Parameter Sets |
|||
1 | 2 | 3 | |
Equilibration temperature () | 80 | 105 | 80 |
Equilibration time (min.) | 60 | 45 | 45 |
Transfer-line temperature () | 85 | 110 | 105 |
Carrier gas: nitrogen or helium at an appropriate pressure | |||
Pressurization time (s) | 30 | 30 | 30 |
Injection volume (mL) | 1 | 1 | 1 |
Organic Volatile Impurity | Limit (µg per g) |
Chloroform | 60 |
1,4-Dioxane | 380 |
Methylene Chloride | 600 |
Trichloroethylene | 80 |
Chromatographic Conditions |
USP Column Designation |
Column Size | Column Temperature |
A | S3 | 3-mm × 2-m | 190 |
B | S2 | 3-mm × 2.1-m | 160 |
C | G16 | 0.53-mm × 30-m | 40 |
D | G39 | 3-mm × 2-m | 65 |
E | G16 | 3-mm × 2-m | 70 |
F | S4 | 2-mm × 2.5-m | Hold 120 (35 min.) Gradient 120200(2/min.) Hold 20 min. |
H | G14 | 2-mm × 2.5-m | Hold 45 (3 min.) Gradient 45120 (8/min.) Hold 15 min. |
I | G27 | 0.53-mm × 30-m | Hold 35 (5 min.) 35175 (8 /min.) 175260(35/min.) Hold 16 min. |
J | G16 | 0.33-mm × 30-m | Hold 50 (20 min.) 50165 (6/min.) Hold 20 min. |
Solvent | Other Names | Structure | Class |
Acetic acid | Ethanoic acid | CH3COOH | Class 3 |
Acetone | 2-Propanone Propan-2-one |
CH3COCH3 | Class 3 |
Acetonitrile | CH3CN | Class 2 | |
Anisole | Methoxybenzene | Class 3 | |
Benzene | Benzol | Class 1 | |
1-Butanol | n-Butyl alcohol Butan-1-ol |
CH3(CH2)3OH | Class 3 |
2-Butanol | sec-Butyl alcohol Butan-2-ol |
CH3CH2CH(OH)CH3 | Class 3 |
Butyl acetate | Acetic acid butyl ester | CH3COO(CH2)3CH3 | Class 3 |
tert-Butylmethyl ether | 2-Methoxy-2-methylpropane | (CH3)3COCH3 | Class 3 |
Carbon tetrachloride | Tetrachloromethane | CCl4 | Class 1 |
Chlorobenzene | Class 2 | ||
Chloroform | Trichloromethane | CHCl3 | Class 2 |
Cumene | Isopropylbenzene (1-Methylethyl)benzene |
Class 3 | |
Cyclohexane | Hexamethylene | Class 2 | |
1,2-Dichloroethane | sym-Dichloroethane Ethylene dichloride Ethylene chloride |
CH2ClCH2Cl | Class 1 |
1,1-Dichloroethene | 1,1-Dichloroethylene Vinylidene chloride |
H2C=CCl2 | Class 1 |
1,2-Dichloroethene | 1,2-Dichloroethylene Acetylene dichloride |
ClHC=CHCl | Class 2 |
1,2-Dimethoxyethane | Ethyleneglycol dimethyl ether Monoglyme Dimethyl cellosolve |
H3COCH2CH2OCH3 | Class 2 |
N,N-Dimethylacetamide | DMA | CH3CON(CH3)2 | Class 2 |
N,N-Dimethylformamide | DMF | HCON(CH3)2 | Class 2 |
Dimethyl sulfoxide | Methylsulfinylmethane Methyl sulfoxide DMSO |
(CH3)2SO | Class 3 |
1,4-Dioxane | p-Dioxane [1,4]Dioxane |
Class 2 | |
Ethanol | Ethyl alcohol | CH3CH2OH | Class 3 |
2-Ethoxyethanol | Cellosolve | CH3CH2OCH2CH2OH | Class 2 |
Ethyl acetate | Acetic acid ethyl ester | CH3COOCH2CH3 | Class 3 |
Ethylene glycol | 1,2-Dihydroxyethane 1,2-Ethanediol |
HOCH2CH2OH | Class 2 |
Ethyl ether | Diethyl ether Ethoxyethane 1,1¢-Oxybisethane |
CH3CH2OCH2CH3 | Class 3 |
Ethyl formate | Formic acid ethyl ester | HCOOCH2CH3 | Class 3 |
Formamide | Methanamide | HCONH2 | Class 2 |
Formic acid | HCOOH | Class 3 | |
Heptane | n-Heptane | CH3(CH2)5CH3 | Class 3 |
Hexane | n-Hexane | CH3(CH2)4CH3 | Class 2 |
Isobutyl acetate | Acetic acid isobutyl ester | CH3COOCH2CH(CH3)2 | Class 3 |
Isopropyl acetate | Acetic acid isopropyl ester | CH3COOCH(CH3)2 | Class 3 |
Methanol | Methyl alcohol | CH3OH | Class 2 |
2-Methoxyethanol | Methyl cellosolve | CH3OCH2CH2OH | Class 2 |
Methyl acetate | Acetic acid methyl ester | CH3COOCH3 | Class 3 |
3-Methyl-1-butanol | Isoamyl alcohol Isopentyl alcohol 3-Methylbutan-1-ol |
(CH3)2CHCH2CH2OH | Class 3 |
Methylbutylketone | 2-Hexanone Hexan-2-one |
CH3(CH2)3COCH3 | Class 2 |
Methylcyclohexane | Cyclohexylmethane | Class 2 | |
Methylene chloride | Dichloromethane | CH2Cl2 | Class 2 |
Methylethylketone | 2-Butanone MEK Butan-2-one |
CH3CH2COCH3 | Class 3 |
Methyl isobutyl ketone | 4-Methylpentan-2-one 4-Methyl-2-pentanone MIBK |
CH3COCH2CH(CH3)2 | Class 3 |
2-Methyl-1-propanol | Isobutyl alcohol 2-Methylpropan-1-ol |
(CH3)2CHCH2OH | Class 3 |
N-Methylpyrrolidone | 1-Methylpyrrolidin-2-one 1-Methyl-2-pyrrolidinone |
Class 2 | |
Nitromethane | CH3NO2 | Class 2 | |
Pentane | n-Pentane | CH3(CH2)3CH3 | Class 3 |
1-Pentanol | Amyl alcohol Pentan-1-ol Pentyl alcohol |
CH3(CH2)3CH2OH | Class 3 |
1-Propanol | Propan-1-ol Propyl alcohol |
CH3CH2CH2OH | Class 3 |
2-Propanol | Propan-2-ol Isopropyl alcohol |
(CH3)2CHOH | Class 3 |
Propyl acetate | Acetic acid propyl ester | CH3COOCH2CH2CH3 | Class 3 |
Pyridine | Class 2 | ||
Sulfolane | Tetrahydrothiophene 1,1-diox- ide |
Class 2 | |
Tetrahydrofuran | Tetramethylene oxide Oxacyclopentane |
Class 2 | |
Tetralin | 1,2,3,4-Tetrahydronaphthalene | Class 2 | |
Toluene | Methylbenzene | Class 2 | |
1,1,1-Trichloroethane | Methylchloroform | CH3CCl3 | Class 1 |
Trichloroethylene | 1,1,2-Trichloroethene | HClC=CCl2 | Class 2 |
Xylene* | Dimethylbenzene Xylol |
Class 2 | |
*
Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene.
|
F1 = | A factor to account for extrapolation between species | |
F1 = | 2 for extrapolation from dogs to humans | |
F1 = | 2.5 for extrapolation from rabbits to humans | |
F1 = | 3 for extrapolation from monkeys to humans | |
F1 = | 5 for extrapolation from rats to humans | |
F1 = | 10 for extrapolation from other animals to humans | |
F1 = | 12 for extrapolation from mice to humans |
F2 = | A factor of 10 to account for variability between individuals. A factor of 10 is generally given for all organic solvents, and 10 is used consistently in this General Chapter. |
F3 = | A variable factor to account for toxicity studies of short-term exposure. | |
F3 = | 1 for studies that last at least one half-lifetime (1 year for rodents or rabbits; 7 years for cats, dogs, and monkeys). | |
F3 = | 1 for reproductive studies in which the whole period of organogenesis is covered. | |
F3 = | 2 for a 6-month study in rodents, or a 3.5-year study in nonrodents. | |
F3 = | 5 for a 3-month study in rodents, or a 2-year study in nonrodents. | |
F3 = | 10 for studies of a shorter duration. |
F4 = | A factor that may be applied in cases of severe toxicity, e.g., nongenotoxic carcinogenicity, neurotoxicity, or teratogenicity. In studies of reproductive toxicity, the following factors are used: | |
F4 = | 1 for fetal toxicity associated with maternal toxicity | |
F4 = | 5 for fetal toxicity without maternal toxicity | |
F4 = | 5 for a teratogenic effect with maternal toxicity | |
F4 = | 10 for a teratogenic effect without maternal toxicity |
F5 = | A variable factor that may be applied if the no-effect level was not established. |
F1 = | 12 to account for the extrapolation from mice to humans |
F2 = | 10 to account for differences between individual humans |
F3 = | 5 because the duration of the study was only 13 weeks |
F4 = | 1 because no severe toxicity was encountered |
F5 = | 1 because the no-effect level was determined |
Rat body weight | 425 g |
Pregnant rat body weight | 330 g |
Mouse body weight | 28 g |
Pregnant mouse body weight | 30 g |
Guinea-pig body weight | 500 g |
Rhesus monkey body weight | 2.5 kg |
Rabbit body weight (pregnant or not) | 4 kg |
Beagle dog body weight | 11.5 kg |
Rat respiratory volume | 290 L/day |
Mouse respiratory volume | 43 L/day |
Rabbit respiratory volume | 1440 L/day |
Guinea-pig respiratory volume | 430 L day |
Human respiratory volume | 28,800 L/day |
Dog respiratory volume | 9000 L/day |
Monkey respiratory volume | 1150 L/day |
Mouse water consumption | 5 mL/day |
Rat water consumption | 30 mL/day |
Rat food consumption | 30 g/day |