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SECTION 1. CHEMICAL IDENTIFICATION

CHEMINFO Record Number: 44
CCOHS Chemical Name: Formamide

Synonyms:
Carbamaldehyde
Methanamide
Formic acid, amide
Formimidic acid
Methanoic acid, amide

Chemical Name French: Formamide
Chemical Name Spanish: Formamida
CAS Registry Number: 75-12-7
RTECS Number(s): LQ0525000
EU EINECS/ELINCS Number: 200-842-0
Chemical Family: Aliphatic amide / aliphatic carboxamide / alkanoic acid amide
Molecular Formula: C-H3-N-O
Structural Formula: H-C(=O)-NH2

SECTION 2. DESCRIPTION

Appearance and Odour:
Clear, colourless to pale yellow, oily, odourless liquid.(33,34) Industrial grades may have a faint odour of ammonia.(35) Hygroscopic (absorbs moisture from the air).(34,36)

Odour Threshold:
Pure formamide is odourless and there is no specific nformation available for industrial grades.

Warning Properties:
POOR - pure formamide is odourless and there is no information available for industrial grades.

Composition/Purity:
Commercial formamide usually has a purity of 99.5% and greater. The principal impurities are methanol (0.1%), ammonium formate (0.1%), water (0.3%), and traces of iron.(33,34,36)

Uses and Occurrences:
Formamide is used as an intermediate in the manufacture of nitrogen-containing heterocyclic compounds (e.g. theophylline, pyrimidine and imidazole), pharmaceuticals, crop protection agents (including fungicides and pesticides), formic acid esters, substituted formamides (e.g. formanilide) and hydrocyanic acid. It is also used as a formylating reagent, e.g. in the N-formylation of primary and secondary amines; as a solvent in the manufacture and processing of plastics; as a solvent for lacquers, wood stains, resins, plasticizers and for ink used in felt- and fibre-tip pens; as an ionizing solvent for many inorganic salts, including chlorides, iodides, nitrates, phosphates, and carbonates; for removing coatings of wire enamel from copper conductors; in the polymerization of unsaturated amines to produce ion-exchange resins and of acrolein and alpha-substituted acroleins to form clear resin solutions used for fabricating films; in the spinning of acrylonitrile copolymers; in the anti-static finishing of plastics and the formation of conductive coatings on plastic particles; as a softener for paper, animal glues and water soluble glues; and as a catalyst in certain synthetic reactions, including carbonylation.(33,34,35)
Until relatively recently, formamide was mainly used to produce formic acid and ammonium sulfate by reaction with sulfuric acid. For environmental reasons, the use of this method is declining.(33,34) It was also formerly used with silicates as a floor sealant, and in de-icing airport runways.(33)


SECTION 3. HAZARDS IDENTIFICATION

EMERGENCY OVERVIEW:
Clear, colourless to pale yellow, oily, odourless liquid. Industrial grades may have a faint odour of ammonia. Hygroscopic. Not combustible. May burn if strongly heated. Can decompose at high temperatures forming extremely toxic hydrogen cyanide and irritating/toxic nitrogen oxides and ammonia. Does not readily form a vapour at room temperature and must be heated or misted before inhalation exposure can occur. Mild to moderate skin irritant, based on limited animal evidence. POSSIBLE REPRODUCTIVE HAZARD - may cause developmental effects, based on animal information.



POTENTIAL HEALTH EFFECTS

Effects of Short-Term (Acute) Exposure

Inhalation:
Formamide does not readily form a vapour at room temperature. Therefore, it must be heated or misted before inhalation exposure can occur. Based on animal studies, exposure to the vapour or mist is unlikely to cause health effects, unless extremely high concentrations are achieved. There is no human information available.

Skin Contact:
Formamide is a mild to moderate irritant, based on limited animal evidence.
Formamide can be absorbed through the skin, but is not expected to be harmful by this route of exposure. There is no human information available.

Eye Contact:
Formamide is a mild eye irritant, based on animal evidence. There is no human information available.

Ingestion:
Formamide is not expected to be toxic if ingested, based on animal toxicity values. There is no human information available. Ingestion is not a typical route of occupational exposure.

Effects of Long-Term (Chronic) Exposure

There is no human information available. The limited animal information available suggests that harmful effects will not occur unless exposures are very high.

Carcinogenicity:

There is no human or animal information available.

The International Agency for Research on Cancer (IARC) has not evaluated the carcinogenicity of this chemical.

The American Conference of Governmental Industrial Hygienists (ACGIH) has not assigned a carcinogenicity designation to this chemical.

The US National Toxicology Program (NTP) has not listed this chemical in its report on carcinogens.

Teratogenicity and Embryotoxicity:
There is no human information available. Formamide has caused developmental toxicity in animals. Formamide caused reduced fetal weight (fetotoxicity) in the offspring of rats and mice exposed to formamide orally, in the absence of maternal toxicity. In rabbits, rats, and mice exposed orally, embryotoxicity (fetal deaths) was observed in the presence of maternal toxicity. In mice exposed to formamide orally, teratogenicity (malformations) was observed in the offspring, but exposure was to "industrial" formamide (composition not specified) and it is not clear that maternal toxicity was thoroughly assessed.
Animal information indicates that formamide will not cause significant developmental toxicity in the absence of maternal toxicity. Formamide has caused reduced fetal weight in rats, in the absence of maternal toxicity. Embryotoxicity was observed in rabbits, in the presence of severe maternal toxicity.

Reproductive Toxicity:
There is no human information available. There is insufficient animal information available to conclude that formamide is a reproductive toxin. In a continuous breeding study using mice, female reproductive toxicity (decreased fertility, decreased litter size, increased days to litter and changes in the reproductive cycle) was observed in the presence of modest changes in body weight (both generations) and increases in food consumption.

Mutagenicity:
There is no human information available. The available information from short-term tests does not indicate that formamide is mutagenic. It was not found to be mutagenic in a dominant lethal test in mice or in tests using bacteria or Drosophila (fruit flies). Positive results (bone marrow micronuclei induction) were reported in mice exposed by intraperitoneal injection. This route of exposure is not relevant to occupational situations.

Toxicologically Synergistic Materials:
There is no information available.

Potential for Accumulation:
Probably does not accumulate. There is no human information available. In rats dosed orally with 2, 3, or 4 g formamide, 27% was excreted in the urine unchanged after 24 hours and a total of 39% after 3 days.(27)


SECTION 4. FIRST AID MEASURES

Inhalation:
If symptoms are experienced, remove source of contamination or move victim to fresh air. Obtain medical advice.

Skin Contact:
As quickly as possible, remove contaminated clothing, shoes and leather goods (e.g. watchbands, belts). Immediately flush with lukewarm, gently flowing water for 15-20 minutes. Immediately obtain medical attention. Completely decontaminate clothing, shoes and leather goods before re-use or discard.

Eye Contact:
Immediately flush the contaminated eye(s) with lukewarm, gently flowing water for 5 minutes, while holding the eyelid(s) open. Obtain medical advice.

Ingestion:
NEVER give anything by mouth if victim is rapidly losing consciousness, is unconscious or convulsing. Have victim rinse mouth thoroughly with water. DO NOT INDUCE VOMITING. If vomiting occurs naturally, have victim rinse mouth with water again. Immediately obtain medical advice.

First Aid Comments:
Consult a doctor and/or the nearest Poison Control Centre for all exposures except minor instances of inhalation or skin contact.
All first aid procedures should be periodically reviewed by a doctor familiar with the material and its conditions of use in the workplace.

Note to Physicians:
NOTE: Formamide is a possible developmental hazard, based on animal information.



SECTION 5. FIRE FIGHTING MEASURES

Flash Point:
154 deg C (310 deg F) (open cup) (28,36); also reported as 175 deg C (347 deg F) (open cup) (33,34)

Lower Flammable (Explosive) Limit (LFL/LEL):
2.7% (33,34)

Upper Flammable (Explosive) Limit (UFL/UEL):
19% (33,34)

Autoignition (Ignition) Temperature:
Greater than 500 deg C (932 deg F) (33,34)

Sensitivity to Mechanical Impact:
Probably not sensitive. Stable material.

Sensitivity to Static Charge:
Formamide will not accumulate static charge since it has a high electrical conductivity.(37,38) Formamide vapour will not be ignited by a static discharge due to its very high flash point.

Electrical Conductivity:
The reported values vary. Electrical conductivity values depend on the purity of formamide, the lower the value, the purer the formamide sample. The reported conductivity of pure formamide varies from 4 X 10(8) pS/m (37,38) to less than 2 X 10(7) pS/m (33,36) at 25 deg C.

Minimum Ignition Energy:
Not available

Combustion and Thermal Decomposition Products:
Formamide begins to decompose when heated above 100 deg C. Appreciable decomposition occurs at 180-190 deg C. The decomposition rate reaches 0.5% per minute at the boiling point (210 deg C). Principal decomposition products are carbon monoxide and ammonia, together with smaller amounts of hydrogen cyanide, water and polymeric hydrogen cyanide derivatives.(33,34) In a fire, carbon monoxide, carbon dioxide, nitrogen oxides, ammonia and hydrogen cyanide are formed.

Fire Hazard Summary:
Formamide is not combustible, but can burn if strongly heated. During a fire, extremely toxic hydrogen cyanide and irritating/toxic nitrogen oxides and ammonia may be generated. Closed containers may rupture violently and suddenly release large amounts of product when exposed to fire or excessive heat for a sufficient period of time.

Extinguishing Media:
Carbon dioxide, dry chemical powder, appropriate foam, water spray or fog. Water or foam may cause frothing.(28) Foam manufacturers should be consulted for recommendations regarding types of foams and application rates.

Fire Fighting Instructions:
Evacuate area and fight fire from a safe distance or a protected location. Approach fire from upwind to avoid hazardous vapours and very toxic decomposition products, like hydrogen cyanide, ammonia and nitrogen oxides.
Water or foam may cause frothing. The frothing may be violent and could endanger personnel close to the fire. However, a water spray or fog that is carefully applied to the surface of the burning material, preferably with a fine spray or fog nozzle, will cause frothing that will blanket and extinguish the fire.(28)
If possible, isolate materials not yet involved in the fire, and move containers from the fire area if this can be done without risk, and protect personnel. Closed containers may rupture violently when exposed to the heat of a fire. Therefore, fire-exposed containers or tanks should be cooled by application of hose streams. Application should begin as soon as possible (within the first several minutes) and should concentrate on any unwetted portions of the container. Apply water from the side and from a safe distance until well after the fire is out. Stay away from ends of tanks, involved in the fire, but be aware that flying material from ruptured tanks may travel in any direction. Withdraw immediately in case of rising sound from venting safety device or any discolouration of tank due to fire. Cooling should continue until well after the fire is out. If this is not possible, use unmanned monitor nozzles and immediately evacuate the area.
If a leak or spill has not ignited, use water spray in large quantities to disperse the vapours and to protect personnel attempting to stop a leak. Water spray can be used to dilute spills to non-flammable mixtures. Dike fire control water for appropriate disposal. Solid streams of water may be ineffective and spread material.
For an advanced or massive fire in a large area, use unmanned hose holder or monitor nozzles; if this is not possible withdraw from fire area and allow fire to burn.
Tanks or drums should not be approached directly after they have been involved in a fire, until they have been completely cooled down. After the fire has been extinguished, toxic atmospheres may linger. Before entering such an area, especially confined areas, check the atmosphere with an appropriate monitoring device while wearing a full protective suit.

Protection of Fire Fighters:
Formamide and its decomposition products (nitrogen oxides, ammonia, hydrogen cyanide) are very hazardous to health. Do not enter without wearing specialized equipment suitable for the situation. Firefighter's normal protective clothing (Bunker Gear) will not provide adequate protection. A full-body encapsulating chemical protective suit with positive pressure self-contained breathing apparatus (NIOSH approved or equivalent) may be necessary.



NATIONAL FIRE PROTECTION ASSOCIATION (NFPA) HAZARD IDENTIFICATION

NFPA - Health: 2 - Intense or continued (but not chronic) exposure could cause temporary incapacitation or possible residual injury.
NFPA - Flammability: 1 - Must be preheated before ignition can occur.
NFPA - Instability: 0 - Normally stable, even under fire conditions, and not reactive with water.

SECTION 9. PHYSICAL AND CHEMICAL PROPERTIES

Molecular Weight: 45.04

Conversion Factor:
1 ppm = 1.84 mg/m3; 1 mg/m3 = 0.54 ppm at 25 deg C (calculated)

Physical State: Liquid
Melting Point: 2.55 deg C (36.6 deg F) (39)
Boiling Point: 210.5 deg C (410.9 deg F) at 101.3 kPa (decomposes) (35,36); also reported as 220 deg C (428 deg F) (38,40)
Relative Density (Specific Gravity): 1.133 at 20 deg C; 1.129 at 25 deg (water = 1) (39,41)
Solubility in Water: Soluble in all proportions.(35,36)
Solubility in Other Liquids: Soluble in all proportions in ethanol, methanol, acetone, acetic acid, dioxane, ethylene glycol, glycerol and phenol; sparingly soluble in most aliphatic hydrocarbons (e.g. hexane), aromatic hydrocarbons (e.g. benzene), chlorinated hydrocarbons (e.g. chloroform), and ethers (e.g. diethyl ether).(34,35,36)
Coefficient of Oil/Water Distribution (Partition Coefficient): Log P(oct) = -1.51 (experimental) (42)
pH Value: 8.5-9.0 (0.1M solution in water); 8.15-8.65 (0.5M); 8.0-8.5 (1M) (calculated)
Acidity: Formamide is both a very weak acid and a very weak base.(43,44,45)
Dissociation Constant: pKa = 16-17.2 (acid) (44,45,46); pKb = approximately 15 (base) (44)
Viscosity-Dynamic: 3.764 mPa.s (3.764 centipoises) at 20 deg C; 3.302 mPa.s (3.302 centipoises) at 25 deg C (39); also reported as 3.23 mPa.s (3.23 centipoises) at 25 deg C (41)
Surface Tension: 58.35 mN/m (58.35 dynes/cm) at 20 deg C; 57.91 mN/m (657.91 dynes/cm) at 25 deg C (39)
Vapour Density: 1.55 (air = 1) (calculated)
Vapour Pressure: 0.008 kPa (0.061 mm Hg) at 25 deg C (40)
Saturation Vapour Concentration: 80 ppm (0.008%) at 25 deg C (calculated)
Evaporation Rate: Not available
Henry's Law Constant: 1.41 x 10(-4) Pa.m3/mol (cited as 1.39 x 10(-9) atm.m3/mol) at 25 deg C (40); log H = -7.24 (dimensionless constant; calculated)

Other Physical Properties:
DIELECTRIC CONSTANT: 111 at 20 deg C (36,38)


SECTION 10. STABILITY AND REACTIVITY

Stability:
Normally stable.(33,34)

Hazardous Polymerization:
Does not occur.

Incompatibility - Materials to Avoid:

NOTE: Chemical reactions that could result in a hazardous situation (e.g. generation of flammable or toxic chemicals, fire or detonation) are listed here. Many of these reactions can be done safely if specific control measures (e.g. cooling of the reaction) are in place. Although not intended to be complete, an overview of important reactions involving common chemicals is provided to assist in the development of safe work practices.


ACIDS (e.g. sulfuric acid) - react vigorously to form formic acid and ammonia, which combine to form ammonium formate.(33,34)
BASES (e.g. sodium or potassium hydroxide) - react vigorously to form alkali formates and ammonia.(33,34)
ORGANOZINC COMPOUNDS (e.g. allylzinc bromide) - adding formamide to a reaction mixture of allylzinc bromide and a ketone caused an uncontrollable explosion-like reaction.(47)

Hazardous Decomposition Products:
Ammonia, formic acid, ammonium formate

Conditions to Avoid:
High temperatures (above 154 deg C)

Corrosivity to Metals:
Formamide is corrosive to unalloyed steel, iron, copper, brass, and lead, especially in the presence of water. It is not corrosive to aluminum and stainless steel.(33,34)

Corrosivity to Non-Metals:
Formamide attacks the plastics thermoset polyester bisphenol-A fumarate and thermoset polyester isophthalic acid (48), and the elastomers Viton A , natural rubber and nylon 12.(34,49) Formamide does not attack plastics, like Teflon, polyvinyl chloride (PVC), nylon and high-density polyethylene (HDPE) (48); and elastomers, like nitrile buna-N (NBR), ethylene propylene, chloroprene, butyl rubber (isobutylene isoprene), neoprene and fluorocarbons, like Chemraz and Kalrez.(34,49)

Stability and Reactivity Comments:
At elevated temperatures, formamide is hydrolyzed in water to give corrosive ammonia and formic acid, which can combine to give ammonium formate.(33,34)


SECTION 11. TOXICOLOGICAL INFORMATION

LC50 (rat): greater than 21000 mg/m3 (4-hour exposure); cited as greater than 21.0 mg/L (4-hour exposure) (1/6 died; nose-only aerosol exposure) (1)
LC50 (rat): greater than 8600 mg/m3 (4-hour exposure); cited as greater than 3900 ppm (6-hour exposure; assumed aerosol exposure) (2, unconfirmed)

LD50 (oral, mouse): 1980 mg/kg* (cited as 1750 microL/kg) (32)
*NOTE: This value is reported as an "average lethal dose" (ALD50).
LD50 (oral, mouse): 3150 mg/kg (cited as 3.15 g/kg) (3, unconfirmed)
LD50 (oral, rat): 6100 mg/kg (cited as 6.1 g/kg) (3, unconfirmed)
LD50 (oral, rat): 6000 mg/kg (cited as 6 g/kg) (4, unconfirmed)
LD50 (oral, rat): 5577 mg/kg (2, unconfirmed)

LD50 (dermal, rat): greater than 17000 mg/kg (5)
Note: This value is described as an "approximate lethal dose" with only one animal/dose.
LD50 (dermal, rabbit): 17000 mg/kg (6, unconfirmed)
Note: This value is reported as an "approximate lethal dose" with no experimental details provided.

Eye Irritation:

Formamide is a mild eye irritant.

Application of 0.1 mL of undiluted formamide caused mild irritation in rabbits (maximum average scores: corneal opacity: 0.7/4 at 4 hours; iris injury: 0.7/2 at 4 hours; redness: 2.3/3 at 24 hours; chemosis 1.3/4 at 4 hours).(7) Application of 0.05 or 0.1 mL of undiluted formamide to rabbits caused mild corneal injury in 2/5, mild inflammation of the iris in 3/5, and mild to moderate irritation in 5/5. Corneal injury was temporary, lasting 24 hours. By the seventh day, 4/5 eyes were normal and the other had minimal irritation.(6) No scoring information was provided. Application of 0.1 mL of undiluted formamide caused severe injury (scored over 5 where 5 is severe injury; graded 4/10).(8)

Skin Irritation:

Formamide is a mild to moderate skin irritant, based on limited information.

Application of undiluted formamide to the intact skin of guinea pigs caused moderate irritation, while a 50% water solution was mildly irritating. On broken skin, 33% and 50% solutions produced mild to moderate irritation.(6) No further details are available.

Effects of Short-Term (Acute) Exposure:

Inhalation:
Rats were exposed nose-only to 0, 1300, 2000, 5100, 14000, 19000, 21000 mg/m3 (cited as 0, 1.3, 2.0, 5.1, 14, 19, or 21 mg/L) formamide aerosol for 4 hours. (Test atmospheres were generated by vapourization or nebulization of formamide. At 19000 and 21000 mg/m3, 88% of the particles had an aerodynamic diameter of less than 10 micrometres and a mass median aerodynamic diameter of 2.8 or 2.9 micrometres). At 21000 mg/m3, 1/6 rats died 11 days after exposure. Signs of toxicity included reduced activity, hunched posture, discharge from the eyes and/or nose, diarrhea and weight loss. Rats exposed to 2000 to 19000 mg/m3, had similar but less severe symptoms. Formamide decomposes to carbon monoxide and ammonia at high temperatures and decomposition may have occurred under the conditions used to generate formamide aerosol in this study.(1) Male rats were exposed to 0, 100, 500 or 1500 ppm formamide vapour for 2 weeks (6 hr/d; 5 d/wk; nose-only exposure). The vapour was generated by heating the formamide to 182 deg C, which may have resulted in decomposition to carbon monoxide and ammonia. The 1500 ppm group had significantly reduced body weights, higher kidney weights, necrosis and regeneration of the kidneys, decreased platelet and lymphocyte counts, and 3/10 rats died. At 500 ppm, the only effect noted was a decreased platelet count. Most of these changes persisted for 2 weeks following exposure.(10) In an unpublished study, rats exposed for 6 hours to 7000 mg/m3 (cited as 3900 ppm) formamide dispersed as a mist, showed no signs of toxicity.(10,11-unconfirmed) No further details are available for evaluation.

Ingestion:
Mice ingested 0, 250, 500, 1000, 2000 or 3000 ppm formamide in drinking water for 2 weeks. Reported doses were 0, 56, 100, 182, 352, and 367 mg/kg/day. A significant decrease in body weight gain was noted at 352 and 367 mg/kg/day. At 367 mg/kg/day, a few animals showed symptoms of reduced activity, squinting, rough coat, hunched back and dehydration.(12) Rats were given oral doses of 0, 34, 113, 340 or 1130 mg/kg/day (cited as 0, 30, 100, 300 or 1000 microL/kg/day) for 4 weeks (5 d/wk). No effects were observed at 34 mg/kg/day. Decreased body weight and changes in some blood parameters were seen at 113 mg/kg/day. At 340 mg/kg/day, 10/20 of each sex died and abnormalities were seen in the digestive tract, spleen, thyroid, thymus, adrenal gland and testes. At 1130 mg/kg/day, all animals died by the end of the first week.(14) Rats and mice were orally exposed to 0, 160, 312, 625, 1250 or 2500 mg/kg/day formamide in water for 2 weeks. General poor health prompted the termination of the study at all doses except 160 mg/kg/day. Animals showed reduced activity, abnormal respiration, incoordination and signs of dehydration and decreased body weights. Decreases in absolute and/or relative thymus, liver, kidney and testis weights were seen in rats and mice exposed to 160 mg/kg/day. No significant gross treatment-related lesions were observed at autopsy (detailed evaluation was not conducted).(9, unconfirmed) When rats were fed 1500 mg/kg/day for up to 2 weeks (5 times/wk), 6/6 animals died. Marked weight loss and inflammation of the stomach were observed.(6) This study is limited by poor reporting and lack of statistical analysis. In an unconfirmed study, female rabbits were given oral doses of 37, 79, 113, 227 mg/kg/day or higher for 13 days. No effects were noted at 37 mg/kg/day. At 79 mg/kg/day, there was a reduction in body weight gain associated with reduced food intake. At 227 mg/kg and above, deaths occurred and there was trembling, weakness in the hind legs, apathy, eye irritation, vaginal discharge, heart and blood changes.(11, unconfirmed)

Effects of Long-Term (Chronic) Exposure:

Skin Contact:
Formamide was applied to the intact skin of rats at doses of 0, 30, 100 and 3000 mg/kg/day for 3 months. No changes were found in animals exposed to 30 or 100 mg/kg/day. At 3000 mg/kg/day, there was redness of the skin, laboured breathing, decreased food consumption and body weight, increased relative weights of the liver and kidneys in both sexes, increased relative weights of the adrenals in males, and death in 3/10 males. There were also a number of changes in blood cell parameters (reduced platelets in males; increased hemoglobin and red blood cells and decreased white blood cells in both sexes).(15) In a similar study, formamide was applied to the intact skin of rats at 0, 300, 1000, and 3000 mg/kg/day for 90 days. The effects at 3000 mg/kg/day were essentially the same as those described above. A slight, but not significant, decrease in body weight gain was seen in males exposed to 300 and 1000 mg/kg/day. At 1000 mg/kg/day, increased hemoglobin and red blood cells, and decreased white blood cells were observed in males.(16)

Ingestion:
Formamide in water was orally administered to rats and mice at doses of 0, 10, 20, 40, 80 or 160 mg/kg/day for 13 weeks. At 80 and 160 mg/kg/day, both mice and rats had significant weight loss. For male mice, a decreasing trend was also noted at the lower doses. In rats, there were increases in red blood cell counts, hemoglobin concentration and hematocrit at the high end of the dose range (specific doses not reported; significance not reported). However, these changes were not consistent between the two species and their toxicological significance was considered small. In mice, possible treatment-related damage was found in the gall bladder and pancreatic duct.(9, unconfirmed) There are insufficient details available to evaluate this study. The lowest published toxic dose for rats is 910 mg/kg given intermittently over 26 weeks (average of 70 mg/kg/day if dosing schedule was 5 days/week). Tests showed impairment of liver function and protein in the urine.(2, unconfirmed)

Skin Sensitization:
An unpublished study found that no skin sensitization occurred when formamide was tested in guinea pigs.(6,17-unconfirmed) No further details are available for evaluation.

Teratogenicity, Embryotoxicity and/or Fetotoxicity:
Formamide has caused developmental toxicity in animals. Formamide caused reduced fetal weight (fetotoxicity) in the offspring of rats and mice exposed to formamide orally, in the absence of maternal toxicity. In rabbits, rats and mice exposed orally, embryotoxicity (fetal deaths) was observed in the presence of maternal toxicity. In mice exposed to formamide orally, teratogenicity (malformations) was observed in the offspring, but exposure was to "industrial" formamide (composition not specified) and it is not clear that maternal toxicity was thoroughly assessed.
In a range-finding study, rats were treated orally with 0, 62, 125, 250, 500 or 1000 mg/kg/day on days 6-19 of pregnancy. Maternal weight gain was reduced at 250 mg/kg/day and higher, and relative liver weights at 500 mg/kg/day and higher. All animals receiving 1000 mg/kg/day were terminated by day 14 due to excessive maternal toxicity. A dose-related decrease in fetal weight was observed, reaching significance at 125 mg/kg/day and higher. No significant effect was noted on the incidence of malformations.(19,20) In the main study, rats were dosed with 0, 50, 100 or 200 mg/kg/day from days 6-19 of pregnancy. There were no maternal deaths and no clinical signs of maternal toxicity. Maternal weight gain was significantly reduced at 200 mg/kg/day, but this effect was attributed to a decrease in uterine weight. There were no significant differences in live litter size, percent resorptions/litter, or late fetal deaths. The average fetal body weight was decreased in a dose-dependent manner, with significance at 100 and 200 mg/kg/day. There was no significant increase in malformations. There was a dose-related increase in the frequency of unossified sternebrae, which has been associated with mild developmental delay.(19,20) Rabbits were orally exposed to 0, 35, 70 and 140 mg/kg/day from day 6-29 of pregnancy. At 35 mg/kg/day, 1/24 mothers died, and at 140 mg/kg/day, 4/24 mothers died. Relative food consumption was reduced at 140 mg/kg/day. Pregnancies were aborted in 2/24 mothers in the 35 and 70 mg/kg/day group and in 8/24 in the 140 mg/kg/day group. No significant differences were observed for the percent resorptions/litter, percent late fetal deaths/litter and percent non-live implants/litter. A significant increasing trend was noted for the percent non-live implants/litter. The number of live fetuses/litter and the average fetal body weight/litter were significantly decreased at 140 mg/kg/day. No significant increase in malformations was noted at any dose.(18) Rats were orally administered 0, 175, 320, 530, 790 or 1590 mg/kg technical grade formamide (cited as 0, 156, 280, 463, 700 or 1400 microL/kg) on days 6-15 of pregnancy. Clinical signs of maternal toxicity were observed at 790 and 1590 mg/kg and deaths occurred at 790 mg/kg. The 1590 mg/kg exposure was terminated early due to maternal toxicity. Maternal weight gain was not statistically evaluated, but animals in the top 4 dose groups showed a lower weight gain than controls. Resorptions were significantly increased at 1590 and 790 mg/kg. The average fetal weight was significantly reduced at all doses. A statistically significant increase in malformations was observed in the offspring of animals exposed to 320-790 mg/kg.(31) Mice were orally exposed to 0, 45, 80, 130, 200 or 400 mg/kg/day "industrial" formamide (cited as 0, 39, 70, 117, 175 or 350 microL/kg/day) on days 6-15 of pregnancy. Clinical signs of toxicity were observed in animals exposed to 400 mg/kg/day and this experimental group was terminated early. No maternal mortality was observed. Weight gain in the mothers was not statistically evaluated, but animals exposed to 400 mg/kg/day showed a lower weight gain, as compared to controls. At 400 mg/kg/day, the number of resorptions was significantly increased. Average fetal body weight was reduced in all exposure groups. Malformations were significantly increased in the offspring of animals exposed to 200 and 400 mg/kg/day.(32) A continuous breeding study using mice exposed to 0, 100, 350, and 750 ppm formamide in drinking water did not show significant developmental effects. Approximate doses were 0, 19, 62 and 172 mg/kg for males and 0, 29, 98, and 218 mg/kg for females.(12,13,21) See "REPRODUCTIVE TOXICITY" below for a review of this study. There are insufficient details available to evaluate the other studies located.(4,5,22)

Reproductive Toxicity:
There is insufficient information available to conclude that formamide is a reproductive toxin. In a continuous breeding study using mice, female reproductive toxicity (decreased fertility, decreased litter size, increased days to litter and changes in the reproductive cycle) was observed in the presence of modest changes in body weight (both generations) and increases in food consumption.
In a continuous breeding study, two generations of mice were exposed to formamide in drinking water at 0, 100, 350, and 750 ppm. Reported approximate doses were 0, 19, 62 and 172 mg/kg/day for males and 0, 29, 98, and 218 mg/kg/day for females. Mice were treated for one-week pre-mating, a 14-week period of male/female co-habitation, and for up to 6 weeks after separation. No significant effects were noted in the first generation mice exposed to 100 or 350 ppm. Exposure to 750 ppm significantly reduced fertility of breeding pairs producing their 5th litter, from 95% (38/40 breeding pairs) in the control, to 65% (13/20 breeding pairs). The number of live pups/litter was significantly reduced by 29% and the number of days to litter was significantly increased. Of those litters born to high-dose pairs, the live pup weight and the percentage born alive were not reduced. Body weight was significantly reduced in males from week 8 and in females from week 16. In a crossover mating trial, it was determined that the female was the most affected sex. Significant differences were observed in the reproductive cycles of 750 ppm females. Second generation mice were continued on the same doses as the parents. Males had reduced body weights at all dose levels and females at 750 ppm. The 750 ppm animals had a significant decrease in fertility rate (60% compared to 89% in controls), and in the number of live pups/litter (27% fewer). A significant decrease in absolute weights of the liver, kidney plus adrenal, and seminal vesicle, and a significant increase in relative weight of the testes were noted at 750 ppm. In females, the weight of the ovaries was significantly reduced at 350 and 750 ppm, and the length of the fertility cycle was greater at 750 ppm.(12,13,21) Rats and mice were orally exposed to 0, 10, 20, 40, 80 and 160 mg/kg/day for 13 weeks. Minimal atrophy of the testes was noted in 4/10 mice in the 160 mg/kg/day group. Degenerate spermatogenic cells were found in the epididymis of 9/10 mice.(9, unconfirmed) No further details are available for evaluation.

Mutagenicity:
The available information does not indicate that formamide is mutagenic.
A negative result was obtained in a limited dominant lethal mutation test in mice exposed intraperitoneally with a single dose of 413 mg/kg.(23) Positive results (bone marrow micronuclei induction) were obtained when male mice were exposed by intraperitoneal injection to 450, 900 or 1800 mg/kg, but not 225 mg/kg, and cells were harvested at 48 hours. Positive results were also obtained following intraperitoneal exposure to 1800 mg/kg with harvesting at 72 hours.(30) This study is reported in a letter and full details are not available. This route of exposure is not relevant to occupational situations.
Negative results (gene mutation) were obtained in tests with bacteria, with and without metabolic activation.(24) Under certain conditions, formamide is considered an appropriate solvent for bacteria mutagenicity testing.(26)
Negative results were also obtained in a test using Drosophila (fruit flies).(25)


SECTION 16. OTHER INFORMATION

Selected Bibliography:
(1) Haskell Laboratories. Inhalation approximate lethal concentration of form amide (sanitized). Date produced: Dec. 18, 1987. E.I. du Pont de Nemours and Company Inc. EPA/OTS 86-880000120S. NTIS/OTS0514010.
(2) MDL Information Systems, Inc. Formamide. Last updated: 2003-08. In: Registry of Toxic Effects of Chemical Substances (RTECS(R)). [CD-ROM]. Canadian Centre for Occupational Health and Safety (CCOHS). Also available at: <ccinfoweb.ccohs.ca/rtecs/search.html> {Subscription required}
(3) Zaeva, G.N., et al. Toxicity of formamide. [Russian]. Toksikol. Novykh Prom. Khim. Veshchestv. No. 9 (1967). p. 163-74. English abstract in: Chemical Abstracts. Vol. 70 (1969). p. 1844
(4) Thiersch, J.B. Effects of acetamides and formamides on the rat litter in utero. Journal of Reproduction and Fertility. Vol. 4 (1962). p. 219-220
(5) Stula, E.F., et al. Embryotoxicity in rats and rabbits from cutaneous application of amide-type solvents and substituted ureas. Toxicology and Applied Pharmacology. Vol. 41, no. 1 (1977). p. 35-55
(6) Toxicity tests on formamide with cover letter dated 081882. Date produced: Feb. 25, 1976. E.I. du Pont de Nemours & Co. EPA/OTS 40-8257013. NTIS/OTS0512666.
(7) Jacobs, G.A. OECD eye irritation tests on two formamides. Journal of the American College of Toxicology. Acute Toxicity Data. Vol. 1 (1992). p. 187-188
(8) Carpenter, C.P., et al. Chemical burns of the rabbit cornea. American Journal of Ophthalmology. Vol. 29 (1946). p. 1363-1372
(9) Kennedy, G.L. Biological effects of acetamide, formamide, and their mono and dimethyl derivatives: an update. Critical Reviews in Toxicology. Vol. 31, no. 2 (Mar. 2001). p. 139-222
(10) Warheit, D.B., et al. Inhalation toxicity study of formamide in rats. Fundamental and Applied Toxicology. Vol. 13, no. 4 (1989). p. 702-713
(11) Formamide and dimethyl formamide: health based recommended occupational exposure limits. Report of the Dutch Expert Committee on Occupational Standards, a committee of the Health Council of the Netherlands, 1995
(12) Final report on the reproductive toxicity of formamide (FORM) (CAS No. 75-12-7) in CD-1 (trade name) Swiss mice. Vol. 1 and 2. US National Toxicology Program, Aug. 1992
(13) Heindel, J., et al. Reproductive toxicology, formamide. Environmental Health Perspectives. Vol. 105, suppl. 1 (Feb. 1997). p. 311-312
(14) Report on the toxicity of formamide after a four-week feed test on rats with cover letter dated 082782. Date produced: Sept. 27, 1982. BASF Wyandotte Corp. EPA/OTS 40-8257006. NTIS/OTS0512660.
(15) BASF AG. Initial submission. Report on the study of the subchronic dermal toxicity of formamide in rats after 3 months administration (final report) with attachments & letter dated 021192. Date produced: May 30, 1985. Monsanto Agricultural Company. EPA/OTS 88-920001301. NTIS/OTS0535890.
(16) Study of subchronic dermal toxicity of formamide in the rat: 90 day study (Project no. 38HO295/8255) with cover letter dated 070984. Date produced: n.d. BASF Wyandotte Corp. EPA/OTS 40-8457062. NTIS/OTS0507213.
(17) American Conference of Governmental Industrial Hygienists (ACGIH). Formamide. In: Documentation of the threshold limit values for chemical substances. 7th ed. American Conference of Governmental Industrial Hygienists, 2001
(18) George, J.D., et al. Evaluation of the developmental toxicity of formamide in New Zealand white rabbits. Toxicological Sciences. Vol. 69 (2002). p. 165-174
(19) Final report on the developmental toxicity of formamide (CAS No. 75-12-7) administered by gavage to Sprague-Dawley CD rats on gestational days 6-19. TER-97-002. NTIS/PB99-139701. US National Toxicology Program, 1998
(20) George, J.D., et al. Evaluation of the developmental toxicity of formamide in Sprague-Dawley (CD) rats. Toxicological Sciences. Vol. 57 (2000). p. 284-291
(21) Fail, P.A., et al., Formamide and dimethyl formamide: reproductive assessment by continuous breeding in mice. Reproductive Toxicology. Vol. 12, no. 3 (1998). p. 317-332
(22) Jelnes, J.E. Health effects of selected chemicals 1. Formamide. Nord. Vol. 6 (1992). p. 9-23
(23) Test report of the mouse dominant lethal assay for mutagenic effects reported at the 2nd Int Symp on chromosome aberrations-October 28-29, 1974 with letter dated 111682. Date produced: n.d. BASF Wyandotte Corp. EPA/OTS 40-8257008. NTIS/OTS0512662.
(24) Mortelmans, K., et al. Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals. Environmental Mutagenesis. Vol. 8, suppl. 7 (1986). p. 1-119
(25) Foureman P., et al. Chemical mutagenesis testing in Drosophila. X. Results of 70 coded chemicals tested for the National Toxicology Program. Environmental and Molecular Mutagenesis. Vol. 23 (1994). p. 208-227
(26) Maron, D., et al. Compatibility of organic solvents with the Salmonella/microsome test. Mutation Research. Vol. 88 (1980). p. 343-350
(27) Bray, H.G., et al. The fate of certain organic acids and amides in the rabbit. 9. Lower aliphatic amides. Biochemical Journal. Vol. 45, no. 4 (1949). p. 467-471
(28) Fire protection guide to hazardous materials. 13th ed. Edited by A.B. Spencer, et al. National Fire Protection Association, 2002. NFPA 325
(29) European Communities (EC). Commission Directive 2001/59/EC. Aug. 6, 2001
(30) BASF Aktiengesellschaft. Initial submission: ltr fr BASF to USEPA w/summary of mouse micronucleus test with formamide, dated 111901. Date produced: Nov. 19, 2001. BASF Corp. EPA/OTS 88020000040. NTIS/OTS0574279.
(31) Report on the examination of formamide for teratogenic effects in rats after oral application with cover letter dated 011183. Date produced: Sept. 24, 1974. BASF Wyandotte Corp. EPA/OTS 40-8357009. NTIS/OTS0512663.
(32) Report on the examination of formamide for the teratogenic effects in mice after oral application XIX/197 with cover letter dated 030783. Date produced: Sept. 24, 1974. BASF Wyandotte Corp. EPA/OTS 40-8357010. NTIS/OTS0512664.
(33) Bipp, H. Formamides: formamide. In: Ullmann's encyclopedia of industrial chemistry. 7th ed. John Wiley and Sons, 2005. Available at: <www.mrw.interscience.wiley.com/ueic/ueic_search_fs.html> {Subscription required}
(34) Höhn, A.. Formamide. In: Kirk-Othmer encyclopedia of chemical technology. John Wiley and Sons, 2005. Available at: <www.mrw.interscience.wiley.com/kirk/kirk_search_fs.html> {Subscription required}
(35) Formamide. The Merck index: an encyclopedia of chemicals, drugs and biologicals. Edited by M.J. O'Neil, et al. 13th ed. Merck and Company, 2001. p. 751-752
(36) Riddick, J.A., et al. Organic solvents: physical properties and methods of purification. 4th ed. Techniques of organic chemistry. Vol. II. John Wiley and Sons, 1986. p. 654-655, 1085-1088
(37) Britton, LG. Using material data in static hazard assessment. Plant/Operations Progress. Vol. 11, no. 2 (Apr. 1992). p. 68
(38) Dean, J.A. Lange's handbook of chemistry. 15th ed. McGraw-Hill, Inc., 1999. p. 1.228, 5.97, 5.118, 8.161
(39) Smith, G.F. The purification and some physical properties of formamide. Journal of the Chemical Society. (1931). p. 3257-3263
(40) Syracuse Research Corporation. The Physical Properties Database (PHYSPROP). Interactive PhysProp Database Demo. Date unknown. Available at: <www.syrres.com/esc/physdemo.htm>
(41) Cases, A.M., et al. Density, viscosity, and refractive index of formamide, three carboxylic acids, and formamide + carboxylic acid binary mixtures. Journal of Chemical and Engineering Data. Vol. 46 (2001). p. 712-715
(42) Syracuse Research Corporation. Interactive LogKow (KowWin) Database Demo. Date unknown. Available at: <syrres.com/esc/kowdemo.htm>
(43) Verhoek, F.H. The strength of acids in formamide. Journal of the American Chemical Society. Vol. 58 (Dec. 1936). p. 2577-2584
(44) Roberts, J.D., et al. Basic principles of organic chemistry. 2nd ed. W.A. Benjamin, Inc., 1977. p. 1175-1176
(45) Homer, R.B., et al. Acid-base and complexing properties of amides. In: The Chemistry of Amides. Edited by J. Zabicky. John Wiley and Sons, 1970. p. 187-188, 238-240
(46) Smith, M.B., et al. March's advanced organic chemistry: reactions, mechanisms, and structure. 5th ed. John Wiley and Sons, 2002. p. 329-331, 343-344
(47) Bretherick's reactive chemical hazards database. [CD-ROM]. 6th ed. Version 3.0. Edited by P.G. Urben. Butterworth-Heinemann Ltd., 1999
(48) Pruett, K.M. Chemical resistance guide for plastics: a guide to chemical resistance of engineering thermoplastics, fluoroplastics, fibers and thermoset resins. Compass Publications, 2000. p. 206-217
(49) Pruett, K.M. Chemical resistance guide for elastomers II: a guide to chemical resistance of rubber and elastomeric compounds. Compass Publications, 1994. p. C-158 to C-163

Information on chemicals reviewed in the CHEMINFO database is drawn from a number of publicly available sources. A list of general references used to compile CHEMINFO records is available in the database Help.


Review/Preparation Date: 2006-01-03



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