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Description of key information

Several acute oral toxicity studies were performed in rats with key lowest LD50 value in adult male and female rats of 1226 and 1053 mg/kg bw , respectively, and 2232 mg/kg bw in male weanling rats. Supporting studies showed oral LD50 value up to 3600 mg/kg bw in rats and 1920 mg/kg bw in mice.

Acute inhalation toxicity was waived based upon the low vapor pressure of Monuron (5.03E-07 mm Hg).

Acute dermal toxicity studies were performed in rats and rabbits, with key LD50 value in adult male and female rats > 2500 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
The data in the present report were accumulated over a period of several years.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Qualifier:
no guideline available
Principles of method if other than guideline:
In general, the methods and procedures used were the same as those used in earlier work (Gaines (1960). The acute toxicity of pesticides to rats. Toxicol. Appl. Pharmacol. 2, 88-99 and
Gaines (1969). Acute toxicity of pesticides. Toxicol. Appl. Pharmacol. 14,515-534.)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
technical grade
Species:
rat
Strain:
Sherman
Remarks:
specific-pathogen-free (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: The rat colony was rederived via cesarean section and maintained under barrier conditions by the U.S. Centers for Disease Control, Atlanta, Georgia. Animals were transferred from the barrier facility at weaning and kept in conventional quarters until used.
- Age at study initiation: Adult animals were at least 90 days of age and weanlings were 4-6 weeks of age when tested.


Route of administration:
oral: gavage
Vehicle:
other: water and oil soluble compounds were given as solutions in water or peanut oil and poorly soluble compounds were given as suspensions in peanut oil
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED:
Adults: Whenever possible the compounds were formulated in varying concentrations and administered in volumes of 5 mL/kg bw. Dosage volumes were routinely 5-10 mL/kg for oral dosing.
Weanlings: Dosage rates up to 20 mL/kg.

Doses:
Minima of 10 animals per group and 4 dosage levels were used for each LD50 calculation.
No. of animals per sex per dose:
Minima of 10 animals per group and 4 dosage levels were used for each LD50 calculation.
Details on study design:
- Duration of observation period following administration: at least 14 days dosing or until recovered from signs of toxicity.
Statistics:
LD50 values and related parameters were calculated using a computer based implementation of Finney’s maximum likelihood probit technique (Lieberman, 1983).
A ratio of greater than 1 indicates greater toxicity to the female compared to the male or greater toxicity to the weanling compared to the adult. The LD50 ratios are considered statistically different from 1 (p < 0.05) when the 95% confidence limits of the LD50 values do not overlap.
Sex:
male
Dose descriptor:
LD50
Remarks:
adult
Effect level:
1 226 mg/kg bw
Based on:
test mat.
95% CL:
> 970 - < 1 642
Remarks on result:
other: slope: 4.2
Sex:
female
Dose descriptor:
LD50
Remarks:
adult
Effect level:
1 053 mg/kg bw
Based on:
test mat.
95% CL:
> 885 - < 1 249
Remarks on result:
other: slope: 4.6
Sex:
male
Dose descriptor:
LD50
Remarks:
weanling
Effect level:
2 232 mg/kg bw
Based on:
test mat.
95% CL:
> 1 911 - < 2 568
Remarks on result:
other: slope: 5.2
Remarks:
LD50 ratio adult/weanling: 0.55 (p<0.05)

Table 1. Acute oral toxicity of Monuron in ratsa

Common name

Ageb

 Sex

Route

LD50(mg/kg)

95% CL

(mg/kg)

Slope

LD50

(M/F)

LD50 Ratio

(A/W)

Monuron

A

M

Oral

1226

970-1642

4.2

 

 

 

A

F

Oral

1053

885-1249

4.6

1.16

 

 

W

M

Oral

2232c

1911-2568

5.2

 

0.55*

a For oral dosing, water and oil soluble compounds were given as solutions in water or peanut oil and poorly soluble compounds were given as suspensions in peanut oil.

Dosage volumes were routinely 5-10 mL/kg for oral dosing. Exceptions to the above are noted.

b A = Adult; W = Weanling.

c Dosage rates up to 20 mL/kg.

* p< 0.05.

Conclusions:
Lowest oral LD50 in adult rats: ca. 1053 mg/kg bw.
Executive summary:

LD50 values were determined for 57 pesticides (among which Monuron) administered by the oral (or dermal) route to adult male and female Sherman rats. Monuron was also tested by the oral route in one sex of weanlings (males). Many of these and earlier LD50 tests have been done in different years and in various months of the year. Since the LD50 value is influenced by variables such as species, strain, and test method, the best estimates of relative toxicity are derived from data collected in a single species and strain under identical conditions. The values for acute toxicity reported here represent the final compilation of data for the LD50 test program whose purpose was to establish a reliable data base on the relative toxicities of pesticidal chemicals in rats, and to obtain other pertinent information including the type, onset, and duration of toxic effects following a single dose.

Except as indicated the compounds were technical grade and were dissolved or suspended in peanut oil for oral dosing (stomach tube). Water and oil soluble compounds were given as solutions in water or peanut oil and poorly soluble compounds were given as suspensions in peanut oil. Whenever possible the compounds were formulated in varying concentrations and administered in volumes of 5 mL/kg body weight for oral dosing. Because of low toxicity or poor solubility of some of the compounds, it was sometimes necessary to adjust the dose volumes as indicated. Adult animals were at least 90 days of age and weanlings were 4-6 weeks of age when tested. Minima of 10 animals per group and four dosage levels were used for each LD50 calculation. The animals were observed for at least 14 days after dosing or until recovered from signs of toxicity. LD50 values and related parameters were calculated using a computer based implementation of Finney’s maximum likelihood probit technique (Lieberman, 1983).

Consistent with previous findings (Gaines, 1960, 1969) the female rat displayed a somewhat greater susceptibility to a number of the chemicals tested. The greater drug metabolizing activity of liver microsomes in the male rat probably accounts for many of the sex-related differences in toxicity which are observed in this species. As expected, nearly all of the compounds were substantially less toxic by the dermal route than by the oral route.

For Monuron female oral LD50 was 1053 mg/kg bw with 95% confidence limits from 885-1249 mg/kg bw and male oral LD50 was 1226 mg/kg bw with 95% confidence limits from 970-1642 mg/kg bw in adult rats.

A number of other studies have demonstrated that susceptibility to the toxicity of chemicals can vary with age. We found that, of 28 chemicals for which adult/weanling oral LD50 ratios were obtained, only 14% were more toxic to the weanling while 64% were more toxic to the adult. The route of exposure may he particularly important in developing animal models of age-related toxicity.

For Monuron male oral LD50 in weanling rats was 2232 mg/kg bw with 95% confidence limits from 1911-2568 mg/kg bw. The LD50 ratio Adult/Weanling was 0.55 (p < 0.05). (Gaines and Linder, 1986).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 053 ng/kg bw
Quality of whole database:
Reliable literature available

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Qualifier:
no guideline available
Principles of method if other than guideline:
In general, the methods and procedures used were the same as those used in earlier work (Gaines (1960). The acute toxicity of pesticides to rats. Toxicol. Appl. Pharmacol. 2, 88-99 and
Gaines (1969). Acute toxicity of pesticides. Toxicol. Appl. Pharmacol. 14,515-534.)
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
technical grade
Species:
rat
Strain:
Sherman
Remarks:
adult specific-pathogen-free (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: The rat colony was rederived via cesarean section and maintained under barrier conditions by the U.S. Centers for Disease Control, Atlanta, Georgia. Animals were transferred from the barrier facility at weaning and kept in conventional quarters until used
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Age at study initiation: Adult animals were at least 90 days of age when tested.
Type of coverage:
not specified
Vehicle:
propylene glycol
Details on dermal exposure:
TEST SITE
- Area of exposure: the freshly shaved shoulder and back area

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):Whenever possible the compounds were administered in volumes of 1.6 mL/kg body weight for dermal dosing. Dosage volumes were routinely 1.6-10 mL/kg for dermal dosing.
- Concentration (if solution): Whenever possible the compounds were formulated in varying concentrations.


No. of animals per sex per dose:
Minima of 10 animals per group and four dosage levels were used for each LD50 calculation.
Details on study design:
- Duration of observation period following administration: The animals were observed for at least 14 days after dosing or until recovered from signs of toxicity.
Statistics:
LD50 values and related parameters were calculated using a computer based implementation of Finney’s maximum likelihood probit technique (Lieberman, 1983).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 500 mg/kg bw

Table 1. Acute dermal toxicity of Monuron in ratsa

Common name

Ageb

 Sex

Route

LD50

(mg/kg)

Monuron

A

M

Dermal

>2500c

 

A

F

Dermal

>2500c

 

 

 

 

 

a For dermal dosing, compounds were usually dissolved in xylene.

Dosage volumes were routinely 5-10 mL/kg for oral dosing and 1.6-10 mL/kg for dermal dosing. Exceptions to the above are noted.

b A = Adult; W = Weanling.

c In propyIene glycol suspension.

Conclusions:
Dermal LD50 for monuron was > 2500 mg/kg.
Executive summary:

LD50 values were determined for 57 pesticides (among which Monuron) administered by the (oral or) dermal route to adult male and female Sherman rats. Many of these and earlier LD50 tests have been done in different years and in various months of the year. Since the LD50 value is influenced by variables such as species, strain, and test method, the best estimates of relative toxicity are derived from data collected in a single species and strain under identical conditions. The values for acute toxicity reported here represent the final compilation of data for the LD50 test program whose purpose was to establish a reliable data base on the relative toxicities of pesticidal chemicals in rats, and to obtain other pertinent information including the type, onset, and duration of toxic effects following a single dose.

Except as indicated the compounds were technical grade and were dissolved or suspended in xylene for dermal application to the freshly shaved shoulder and back area. Monuron was suspended in propylene glycol. Whenever possible the compounds were formulated in varying concentrations and administered in volumes of 1.6 mL/kg body weight for dermal dosing. Because of low toxicity or poor solubility of some of the compounds, it was sometimes necessary to adjust the dose volumes as indicated. Dosage volumes were routinely 1.6-10 mL/kg for dermal dosing.

Adult animals were at least 90 days of age and weanlings were 4-6 weeks of age when tested. Minima of 10 animals per group and four dosage levels were used for each LD50 calculation. The animals were observed for at least 14 days after dosing or until recovered from signs of toxicity. LD50 values and related parameters were calculated using a computer based implementation of Finney’s maximum likelihood probit technique (Lieberman, 1983).

As expected, nearly all of the compounds were substantially less toxic by the dermal route than by the oral route.

For Monuron dermal LD50 was > 2500 mg/kg bw in male and female adult rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 500 mg/kg bw
Quality of whole database:
Reliable literature available

Additional information

Acute oral toxicity

Key LD50 values were determined for Monuron administered by oral gavage to adult male and female Sherman rats and in one sex of weanling rats (males). Adult animals were at least 90 days of age and weanlings were 4-6 weeks of age when tested. In adult rats, female oral LD50 was 1053 mg/kg bw with 95% confidence limits from 885-1249 mg/kg bw and male oral LD50 was 1226 mg/kg bw with 95% confidence limits from 970-1642 mg/kg bw in adult rats. In weanling rats, male oral LD50 in weanling rats was 2232 mg/kg bw with 95% confidence limits from 1911-2568 mg/kg bw (Gaines and Linder, 1986).

Supporting studies provided following oral LD50 values:

- LD50 = 1480 mg/kg bw in rats (NTP, 1988).

- LD50 = 1480-3700 mg/kg bw in rats (IARC, 1991).

- LD50 = 3600 mg/kg bw with confidence limits of 2800 to 4400 mg/kg (US EPA, 1975).

- LD50 = 1920 mg/kg in mice (NTP, 1988).

 

Acute inhalation toxicity

Based upon the low vapor pressure of Munuron (5.03E-07 mm Hg), acute inhalation toxicity testing was waived.

 

Acute dermal toxicity

A key LD50 values was determined for Monuron administered by the (dermal route to adult male and female Sherman rats. Adult animals were at least 90 days of age. For Monuron dermal LD50 was > 2500 mg/kg bw in male and female adult rats. (Gaines and Linder, 1986). Based on this value, Monuron was less toxic by the dermal route than by the oral route.

Supporting studies provided following dermal LD50 values:

- LD50 > 2500 mg/kg bw in rabbits (IARC, 1991).

- A 20% suspension of monuron in dimethyl phthalate was applied to shaved skin between the shoulders of a male rabbit. A maximum feasible dose of 2250 mg/kg was administered over an 8-hr period by rubbing it into the skin with a glass rod. Five hours after treatment, the material was caked on the rabbit' s back. The material disappeared within 2 days, and the rabbit showed no clinical signs of intoxication. No significant clinical pathology was found at sacrifice, 11 days after treatment (US EPA, 1975).

Justification for classification or non-classification

Based on these results and according to CLP (No. 1272/2008 of 16 December 2008), Monuron has a harmonised classification Category 4 (H302. Harmful if swallowed) for acute oral toxicity with signal word 'WARNING'.

Based on these results and according to CLP (No. 1272/2008 of 16 December 2008), Monuron does not have to be classified and has no obligatory labelling requirement for dermal toxicity.