Ferbam

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: expert statement

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: An extensive assessment of the toxicokinetic behaviour of the registered substance was performed, taking into account the chemical structure, the available physico-chemical and toxicological data.

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Qualifier:

no guideline followed

Principles of method if other than guideline:

An extensive assessment of the toxicokinetic behaviour of ferbam was performed, taking into account the chemical structure, the available physico-chemical and toxicological data.

GLP compliance:

no

Route of administration:

other: all relevant routes of administration are discussed in the expert statement

Type:

absorption

Results:

Ferbam is well absorbed to a large extent (up to 70%) by the GI tract. Also absorption after inhalation seems to be substantial, while dermal absorption is low

Type:

distribution

Results:

Ferbam is systemically distributed

Type:

metabolism

Results:

It hydrolyses readily into dimethyldithiocarbamate and the iron ion Fe3. Dimethyldithiocarbamate is metabolized by hepatic conjugation with glucuronic acid and by gut decomposition to diethylamine and carbon disulphide

Type:

excretion

Results:

The metabolites are primarily excreted in urine, but carbon disulphide is also exhaled.

Characterisation of the toxicokinetics of Ferbam

 

Data availability

The toxicokinetics of Ferbam have been investigated in an experimental study by Hodgson et al. (1975), which was used as the primary information source, as it was done in similar evaluations, e.g. by the German MAK commission (MAK, 2012). The characterisation of the toxicokinetics was supported by several experimental studies informingaspects of adsorption, distribution, metabolism and excretion.

In addition, toxicokinetic information from the structurally closely related analogue Ziram was considered, primarily when data on Ferbam were lacking. Both Ferbam and Ziram are dithiocarbamates with the same core molecule dimethyl dithiocarbamate. This is justified as the two substances differ only in the number of dimethyldithiocarbamate (Ferbam: 3; Ziram: 2) and the metal ion (Ferbam: Fe; Ziram: Zn) and that their metabolism is similar in mammalian systems. In acidic media, as in the stomach, the substances dissociate into dimethyldithiocarbamate and the respective ions, which are both essential nutrients.

 

 

Physicochemical properties

Focusing on the main physicochemical parameters that can inform the toxicokinetic properties of a substance, Ferbam has a water solubility of 1.4 mg/L and a low octanol-water partitioning coefficient (log Pow of -1.6). It has a very low vapour pressure. It hydrolyses quickly, e.g. it has a half-life of 12 minutes at 25°C and a pH of 5, as experimentally determined in a GLP-compliant study according to EPA Guideline Subdivision N 161-1 (see respective study record by Nixon, 1996).Hydrolysis half-lifes decrease for increasing pH. A comprehensive overview of the physicochemical properties of Ferbam, together with substance identity information, is given in Table 1. In this table, the corresponding information for Ziram has been included.

 

		Ferbam	Ziram^1
Substance identity information	EC number	238-484-2	205-288-3
	CAS number	14484-64-1	137-30-4
	IUPAC name	iron(3+) tris(dimethyldithio-carbamate)	zinc bis(dimethyldithio-carbamate)
	Molecular structure
	Molecular formula	C9H18FeN3S6	C6H12N2S4Zn
	Molecular weight	416.4943	305.8419
	Purity	98-100%	98-100%
Physico-chemical properties	Appearance	dark brown to black, odorless solid	white solid with a sweet and musty odor
	Melting point	decomposition at 180°C	251 – 252.5°C
	Boiling point	decomposition at 180°C	not available
	Relative density	0.21	1.71
	Particle size (Granulometry)	Median mass diameter: 0.25 – 0.5 mm	Median mass diameter: 2.33 µm
	Vapour pressure	0.0001164 Pa (at 25°C)	0.000018 Pa (at 20°C)
	Partition coefficient	-1.5972 (at 20°C)	-1.65 (at 20°C)
	Water solubility	5 mg/L (at 20°C)	0.97 mg/L (at 20°C)
	Surface tension	74.3 mN/m (at 20°C)	73 mN/m (at 16°C)
	Auto flammability	not self-igniting	not self-igniting
	Flammability	not flammable	not flammable
	Explosiveness	not explosive	not explosive
	Oxidising properties	not oxidising	not oxidising

 

Table 1: Overview of substance identity information and physicochemical properties for Ferbam and Ziram

¹Information obtained on March 2, 2018, from the disseminated REACH dossier, available at https://echa.europa.eu/de/registration-dossier/-/registered-dossier/2153

 

 

Toxicological profile of Ferbam

Ferbam was not acutely toxic via the oral route in a study according to EPA OPP 81-1 (see respective study record by Reijnder, 1987a) and via the dermal route in a study according to EPA OPP 81-2 (see respective study record by Reijnder, 1987b). In contrast, it induced mortality associated with local effects (pulmonary oedema and haemorrhage) and other signs of acute toxicity in acute inhalation studies (according to EPA OPP 81-3) for concentration higher than 0.15 mg/L (see respective study records by McDonald, 1988 and by Hardy, 1988). It was very slightly skin irritating in a study according to EPA OPP 81-5 (see respective study record by Weterings, 1987a) and induced only very slight eye irritation in a study according to EPA OPP 81-4 (see respective study record by Weterings, 1987b). However, it has been classified as ‘Skin Irrit. 2’ (H315) and as ‘Eye Irrit. 2’ (H319) in the harmonised classification according to the CLP regulation. Ferbam did not induce skin sensitization in a GLP-study according to EPA OPP 81-6 (see respective study record by Weterings, 1987c). It was positive in a bacterial reverse mutation test according to OECD Test Guideline 471, significantly increasing the number of revertant colonies in Salmonella typhimurium strains TA 1535, TA 102 and TA 100 (see respective study record by Bowles, 2002). Based on a negativein vitrogene cell mutation test according to OECD TG 476 (see respective study record by Ransome, 1999), a negativein vivomammalian erythrocyte micronucleus according to OECD TG 474 (see respective study record by Proudlock, 1992) and a negativein vivomammalian spermatogonial chromosome aberration test according to OECD TG 483 (see respective study record by Völkner, 1992) with Ziram, this result is considered false positive. Therefore, Ferbam is neither mutagenic nor genotoxic. No repeated dose toxicity studies and no studies investigating the toxicity to reproduction are available for Ferbam. The information requirements have been met by read-across to respective studies conducted with Ziram. The key study for systemic effects is a sub-chronic, i.e. 90 days, feeding study with Beagles according to OECD TG 409 administering the doses of 4.07, 12.21 and 40.7 mg kg/bw per day (see respective study record by McLean, 1992b). This study showed liver effects, such as minimal focal necrosis and pigmented Kupffer cells, in the mid and high dose group, resulting in a NOAEL of 4.07 mg/kg bw. NOAELs determined in a two-generation reproduction toxicity study according to OECD TG 416 testing Ziram at 2.93, 8.2 and 22.0 mg/kg bw (see respective study record by Nemec, 1996) were higher (parental systemic toxicity and neonatal toxicity NOAEL: 8.2 mg/kg bw; reproductive and developmental neurotoxicity NOAEL: 22.0 mg/kg bw) compared to the 90-days Beagle study by McLean (1992b). Note that all studies referred to here were GLP-compliant and reliable without restriction, except for the OECD TG 474 study by Proudlock (1992), which was reliable with restrictions.

 

 

 

Toxicokinetics of Ferbam

 

Absorption

Oral/gastrointestinal

With a half-life of 12 minutes, Ferbam hydrolysed rapidly at a pH of 5 and at 25°C in a GLP-compliant study according to EPA Guideline Subdivision N 161-1 (see respective study record by Nixon, 1996), forming organic hydrolysis products and the iron ion Fe³⁺. As iron is an essential nutrients, it is not relevant for the toxicokinetics and not further considered.

Hodgson et al. (1975), who applied a single doses (500 mg/kg) of radiolabelled [³⁵S]Ferbam and of radiolabelled [¹⁴C]Ferbam suspended in 0.5% carboxymethyl cellulose to rats by an intragastric tube, found that 40% to 70% was absorbed from the gastrointestinal (GI) tract. Consistent with the rapid hydrolysis, they propose that in the gut Ferbam forms dimethyldithiocarbamate, which is either absorbed as such or after decomposition as dimethylamine and carbon disulphide (CS₂) (Figure 1).
These experimental findings are supported by the interpretation of structural and physicochemical properties regarding the oral/GI absorption. The molecular weight of 416.5 (< 500), the slight water solubility (5 mg/L) and the log Pow (octanol-water partition coefficient) of -1.6 favour at least some absorption by passive diffusion. In addition, Ziram is well absorbed from the rat GI tract within 48 hours after oral administration for (58-61% after a single low dose (15 mg/kg bw), 60-69% after a single high dose (352 mg/kg bw) and for 71-75% after a repeated low dose (15 mg/kg bw)), resulting in an overall oral absorption of 66% (Cheng, 1989).

 

Inhalation

In the absence of data for Ferbam and also the analogue Ziram, it is assumed that the hydrolysis products of Ferbam, which are relevant for the toxicokinetics, are also well absorbed by the respiratory tract. This is indirectly supported by the acute inhalation toxicity (LC50: 0.281 mg/L) observed in a GLP-compliant and reliable acute inhalation study with Ferbam (see respective study record by McDonald, 1988), which triggered a self-classification as ‘Acute Tox. 2 (H330: Fatal if inhaled)’, and also the repeated dose inhalation toxicity (Brooker, 2001) of Ziram.

The vapour pressure is with 0.0001164 Pa very low (see respective study record by Lemal, 1986) and the proportion of particles smaller than 100 µm, i.e. particles potentially inhalable by humans, determined by Pessin (1999) (see respective study record) summed up to 7.33% (7.19% between 53 and 106 µm and 0.14% smaller than 53 µm). While these two factors do not support inhalation absorption, the slight water solubility (5 mg/L) and the log Pow (octanol-water partition coefficient) of -1.6 favour at least some absorption by passive diffusion.

 

Dermal

While no dermal absorption data are available for Ferbam, dermal absorption has been investigated for Ziram. In a GLP-compliant reliable study using human skinin vitroaccording to OECD TG 428, a maximum dermal absorption of 2.2% was found after 6 hours of exposure for the two doses 0.016 mg/cm²and 6.4 mg/cm²(Kane, 2006). In addition, absorption rates between 0.56% and 8.88% were reported in a GLP-compliant and reliable study according to OECD TG 427, in which three single doses (0.086, 0.95 and 7.25 mg/cm²) were applied to rat skin in vivo and absorption measured after 0.5, 1, 2, 4, 10 and 24 hours (Cheng, 1991).

The physical-chemical parameters that influence the dermal absorption support these experimental findings of low dermal absorption. While the molecular weight of Ferbam does not allow to exclude dermal absorption, the water solubility of 5 mg/L is associated with low to moderate dermal absorption. As Ziram has a similar molecular weight and water solubility (0.907 mg/L), it can be assumed that Ferbam has a similar dermal absorption rate as Ziram, i.e. approx. 10% or lower.

 

 

Distribution

After absorption via the gastro-intestinal tract, the results of Hodgson et al. (1975) suggest that Ferbam is systemically distributed, but readily metabolized and excreted. The distribution to various organs and excretion is summarised in Table 2.

 

 

	[^35S]Ferbam			[^14C]Ferbam
	% of administered dose after			% of administered dose after
	4h	12h	24h	4h	24h
GI tract (incl. contents)	70.4±9.5 (3)	67.1±10.2 (2)	38.6±12.9 (4)	76.2±7.1 (3)	9.8±3.1 (3)
feces	0.4±0.3 (3)	3.4±0.9 (2)	16.9±7.1 (4)	11.6±1.4 (2)	20.0±7.5 (3)
urine	1.3±0.9 (3)	9.6±1.6 (2)	22.7±8.7 (4)	3.9±1.0 (3)	42.9±4.1 (3)
expired air	1.0±0.4 (3)	12.4±0.4 (2)	18.1±2.9 (4)	< 0.1 (3)	0.6±0.2 (3)
whole blood	0.3±0.0 (3)	0.8±0.1 (2)	0.6±0.1 (4)	0.4±0.1 (3)	0.9±0.2 (3)
liver	0.3±0.1 (3)	0.5±0.2 (2)	0.3±0.1 (4)	0.6±0.2 (3)	0.7±0.1 (3)
kidneys	< 0.1 (3)	0.15±0.04 (2)	0.1±0.0 (4)	0.2±0.0 (3)	0.2±0.0 (3)
muscle	3.1±0.6 (3)	1.8±0.2 (2)	1.9±0.5 (4)	2.0±0.7 (3)	2.0±0.4 (3)
brain	< 0.1 (3)	0.1±0.0 (2)	< 0.1 (4)	< 0.1 (3)	< 0.1 (3)
total recovery	76.8±11.2	95.8±10.6	98.4±8.7	91.0±6.7	77.1±10.0
bile	0.2±0.0 (3)	0.5±0.0 (3)	1.0±0.2 (3)	0.3±0.0 (5)	1.4±0.3 (5)

 

Table 2: Distribution of radiolabeled Ferbam in rats as mean %±standard error and number of rats in brackets(reproduced from Tables 1 and 2 ofHodgson et al., 1975)

 

 

During 24 hours after administration of a single dose, only small amounts of radioactivity were found in organs, such as the kidney, liver, skeletal muscle and brain with no time-related trend (Hodgson et al., 1975). When administered to pregnant rats, radioactivity was distributed equally to the placenta, the fetus, amnionic fluid and the maternal plasma (Hodgson et al., 1975). In lactating rats, radioactivity was secreted into milk, absorbed by the pups and excreted in pup urine (Hodgson et al., 1975).

The systemically distribution is supported by the molecular weight of the hydrolysis and decomposition products, which potentially allow for wide distribution, and by the water solubility allowing for diffusion. As the log Pow is smaller than 0, distribution into cells is unlikely.

The data of Table 2 also indicate that Ferbam has no potential to bioaccumulate. This is supported by the physico-chemical properties. With a log POW of -1.6, Ferbam will not concentrate in adipose tissue and not persist in the stratum corneum of the skin. The very low proportion of small particles, i.e. < 1 µm, suggests that Ferbam has also no potential to deposit in the alveolar region in the lung.

A finding, which is supported by data on Ziram, which, after repeated exposure (15 days), was recovered from tissues and carcasses of rats in low amount (< 2%) only (Cheng, 1989).

 

In the absence of data, the distribution is assumed to be at least similar, when Ferbam is absorbed by the respiratory tract and the skin.

 

 

Metabolism

The metabolism of Ferbam has been described by INCHEM(http://www.inchem.org/documents/jmpr/jmpmono/v96pr06.htm), which is based on an unpublished report by Lee et al. (1975). Equivalent to the metabolism of Ziram, the dimethyldithiocarbamate is metabolized through two separate pathways (Figure 1):

A) conjugation with glucuronic acid, indicating that some dimethyl dithiocarbamate is absorbed from the gut intact, and

B) decomposition to diethylamine and carbon disulphide, probably in the gut (Hodgson et al., 1975).

 

Excretion

The excretion over 24 hours after administration of a single dose of Ferbam has been studied by Hodgson et al. (1975) using [³⁵S]Ferbam and [¹⁴C]Ferbam. After 24 hours [¹⁴C]Ferbam has excreted to a large extend through the feces (20%) and the urine (43%), but not through exhalation (Table 2), linking this excretion pattern to the glucuronisation metabolism pathway. [³⁵S]Ferbam has been excreted after 24 hours to about 20% each through feces, urine and exhalation, which provides evidence for the decomposition pathway, which inter alia results in exhalation of carbon disulphide. The Ferbam metabolites glucoronated dimethyldithiocarbamate and dimethylamine are excreted through urine, while carbon disulphide is both exhaled and extracted through in the urine (Figure 1). As only minor amount of radioactivity was found in the bile, the biliary system is a minor excretion route (Hodgson et al., 1975).Not absorbed Ferbam was excreted in feces.

 

References

Brooker, A.J. (2001).Ziram technical: 28 day repeat dose snout only inhalation toxicity study in rats with a 28 day reversibility period. Unpublished study report; robust study summary available at https://echa.europa.eu/de/registration-dossier/-/registered-dossier/2153/7/6/3 (last accessed on March 3, 2018)

Cheng, T. (1989). Metabolism of Ziram in Rats. Unpublished study report; robust study summary available at https://echa.europa.eu/de/registration-dossier/-/registered-dossier/2153/7/6/3 (last accessed on March 3, 2018)

Cheng, T. (1991). Dermal absorption of 14C-Ziram in Male Rats. Unpublished study report; robust study summary available at https://echa.europa.eu/de/registration-dossier/-/registered-dossier/2153/7/6/3 (last accessed on March 3, 2018)

Hodgson, J.R., Hoch, J.C., Castels, T.R., Helton, D.O., Lee, C.C. (1975). Metabolism and disposition of ferbam in the rat. Toxicol Appl Pharmacol 33(3): 505-513.

Kane, T.J. (2006).Ziram (76 WG) - In Vitro Dermal Penetration Study At Two Dose Levels Using Human Skin.Unpublished study report; robust study summary available at https://echa.europa.eu/de/registration-dossier/-/registered-dossier/2153/7/6/3 (last accessed on March 3, 2018)

Lee, C.-C., Russell, J.Q., Minor, J.L., Kowalski, J.J., Sanyer, J.L., Kintner, L.D., Hodgson, J.R., Short, R.D., Peters, P.J., Dilley, J.V., Murrill, E.A., Holton, D.O. & Ellis, H.V. (1975). Toxicological evaluation of ferric dimethyldithiocarbamate (ferbam) and dithio-carbamate (thiram) with acute toxicity of manganese and zinc ethylene-bisdithiocarbamates (maneb and zineb). Unpublished report No. 3612-B from National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Submitted to WHO by UCB Chemicals, Belgium.

MAK (2012). Ferbam (MAK Value Documentation, 2003). The MAK Collection for Occupational Health and Safety. 164-168.

Executive summary:

Ferbam is well absorbed to a large extent (up to 70%) by the GI tract. Also absorption after inhalation seems to be substantial, while dermal absorption is low. It hydrolyses readily into dimethyldithiocarbamate and the iron ion Fe³⁺. As iron is an essential nutrient, it is not relevant for the further characterization of the toxicokinetics of Ferbam. Dimethyldithiocarbamate is metabolized by hepatic conjugation with glucuronic acid and by gut decomposition to diethylamine and carbon disulphide. These metabolites are primarily excreted in urine, but carbon disulphide is also exhaled.

Description of key information

Ferbam is well absorbed to a large extent (up to 70%) by the GI tract. Also absorption after inhalation seems to be substantial, while dermal absorption is low. It hydrolyses readily into dimethyldithiocarbamate and the iron ion Fe³⁺. As iron is an essential nutrient, it is not relevant for the further characterization of the toxicokinetics of Ferbam. Dimethyldithiocarbamate is metabolized by hepatic conjugation with glucuronic acid and by gut decomposition to diethylamine and carbon disulphide. These metabolites are primarily excreted in urine, but carbon disulphide is also exhaled.

Key value for chemical safety assessment

Absorption rate - oral (%):

70

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100