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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Only limited details were available from a three-generation reproductive toxicity study with Monuron in rats dosed via the diet at 0, 125, and 2500 ppm. Up to 2500 ppm, no effects were observed, except for some lower litter sizes in 6 litters. As there were no details, the study was considered to be supportive and additional data were investigated from read-across substance Diuron.

Diuron was tested in a two-generation reproduction study in rats via the diet at 0, 10, 250 or 1750 ppm. Parental toxicity was observed at 1750 ppm in the first and second generation and decreased pup body weight was observed in the F1 and F2 pups as the only reproductive effect. The NOEL for parental and reproductive toxicity was 250 ppm (16.9-20.3 mg/kg/day in males/females, respectively)., leading to a ‘target NOAEL’ of 14.4 mg/kg bw. Reproductive findings were considered secondary non-specific effects.to the parental toxicity.

Supporting reproductive toxicity studies in adult rats with Diuron further demonstrated that there were no effects plasma testosterone, daily sperm production & reserves, sperm morphology or male sexual behaviour after 30 days treatment up to 250 mg/kg bw by oral gave, and that after treatment during lactation up to 750 ppm in the diet of male rats up to 90 days of age, there were only some reductions in body weight but no reproductive-system alterations (reproductive organ weights, sperm parameters, plasma testosterone levels, and testicular and epididymal histopathology).

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
see read across justification attached to section 13
Reason / purpose:
read-across source
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No compound-related clinical signs were observed in any sex and generation.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
In the Fo generation, one female from the control group was sacrificed in extremis due to difficulties at the time of delivery.
One female from the 10-ppm group was found dead; necropsy did not reveal cause of death.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Compound-related effects in body weight and body weight gain were observed at 1750 ppm in both sexes.
Among males at 1750 ppm body weight decreased significantly by an average of 7% starting on day 7. Body weight gain among males decreased significantly at 250 ppm on days 91-98 (18%) and at 1750 ppm on days 0-14 (21%), 21-28 (15%), 42-49 (28%), 77-84 (53%), 91-98 (90), 0-70 (premating; 16%), 70-112 (mating and postmating; 28%), and 0-112 (entire feeding period;18%).
Among females at 1750 ppm, body weight decreased significantly by an average of 7% starting on day 7 during premating and by 9% during the gestation and lactation periods. Body weight gain among females decreased significantly at 1750 ppm on days 0-7 (48%), 21-28 (69%), and 0-70 (premating; 28%).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Among males at 1750 ppm food consumption (g/animal/day) decreased significantly on days 0-14, 21-28, 42-56, and 0-70.
Among females at 1750 ppm food consumption decreased significantly on days 0-7, 21-28, 35-49, and 0-70. During gestation food consumption decreased consistently at 1750 ppm.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Compound-related effects on food efficiency were observed at 1750 ppm in both sexes.
Food efficiency among males decreased significantly at 10 ppm on days 42-49 and at 1750 ppm on days 0-14,42-49, and 0-70. It increased significantly at 10 ppm on days 63-70; at 250 ppm on days 35-42 and 63-70; and at 1750 ppm on days 63-70.
Food efficiency among females decreased significantly at 1750 ppm on days 0-7, 21-28, and 0-70. It increased significantly at 10 ppm on days 0-7. During gestation no differences between groups were noted in food efficiency.
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No compound-related histologic findings were observed for any sex and generation.
Histopathological findings: neoplastic:
no effects observed
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
Fertility index significantly increased at 1750 ppm due to a low fertility index in the control group.
Dose descriptor:
NOEL
Effect level:
250 ppm
Based on:
test mat.
Remarks:
Diuron
Sex:
male/female
Basis for effect level:
other: parental toxicity
Dose descriptor:
LOEL
Effect level:
1 750 ppm
Based on:
test mat.
Remarks:
Diuron
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Clinical signs:
no effects observed
Description (incidence and severity):
No compound-related clinical signs were observed in any sex and generation.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No compound-related mortalities were observed.
In the F1 generation, three males, one each from the control group, 250-ppm group, and 1750-ppm group were found dead. The control animal had kidney cysts; necropsies of the other two males did not reveal cause of death.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Compound-related effects in body weight and body weight gain were observed at 1750 ppm in both sexes and generations.
Among males at 1750 ppm body weight decreased significantly by an average of 16% starting on day 0. Body weight gain among males decreased significantly at 250 ppm on days 63-70 (33%) and 147-154 (52%) and at 1750 ppm on days 0-28 (16%), 42-49 (20%), 63-70 (26%), 91-98 (46%), 147-154 (72%), 0-105 (premating; 15%), 105-161 (mating and postmating; 41%), and 0-161 (entire feeding period; 17%).
Among females at 1750 ppm body weight decreased significantly by an average of 16% starting on day 0 during premating; by 14% during the gestation period; and by 19% during the lactation periods. Body weight gain among females decreased significantly at 250 ppm on days 0-7 (11%) and 14-21 (12%) and at 1750 ppm on days 0-14 (17%) and 0-105 (premating; 14%); it increased significantly at 10 ppm on days 70-77. During gestation, body weight gain decreased significantly on days 14-21 (21%) and 0-21 (19%). During the lactation period, significant increases in body weight gain were observed at 1750 ppm on days 0-7, 14-21, and 0-21.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Among males at 1750 ppm food consumption consistently decreased significantly (with the exception of days 77-84). It increased significantly at 10 ppm on days 84-91.
Among females food consumption decreased significantly at 10 ppm on days 91-98; at 250 ppm on days 7-14, 21-35, 56-63, 91-105, and 0-105; and at 1750 ppm during the entire premating. During gestation, food consumption decreased consistently at 1750 ppm
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Compound-related effects on food efficiency were observed at 1750 ppm in F1 females.
Among males food efficiency decreased significantly at 1750 ppm on days 91-98 ; Iamong females food efficiency decreased significantly at 1750 ppm on days 0-7, 21-28, and 0-70 and increased significantly at 10 ppm on days 70-77. During gestation no differences between groups were noted in food efficiency.
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Testis weights: No compound-related effects were observed for any generation. At 1750 ppm, relative (percent of body weight) testis weight significant1y increased in both generation males, which was due to decreased body weight rather than caused by the test compound. An incidental significant increase was noted in absolute testis weight at 10 ppm in F1 males.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No compound-related gross findings were observed for any sex and generation.
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No compound-related histologic findings were observed for any sex and generation.
Histopathological findings: neoplastic:
no effects observed
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Dose descriptor:
NOEL
Effect level:
250 ppm
Based on:
test mat.
Remarks:
Diuron
Sex:
male/female
Basis for effect level:
other: parental NOEL
Dose descriptor:
LOEL
Effect level:
1 750 ppm
Based on:
test mat.
Remarks:
Diuron
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Clinical signs:
no effects observed
Description (incidence and severity):
No compound-related effects were noted in pup clinical observations.
Mortality / viability:
no mortality observed
Description (incidence and severity):
No compound-related effects were noted in pup survival.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Pup body weight for sexes combined or separated significantly decreased at 1750 ppm on lactation days 7, 14, and 21; this was considered to be a compound-related effect.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In males food consumption decreased significantly.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
In males food consumption decreased significantly in week 91-98.
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
No compound-related effects were noted in pup anomalies.
Histopathological findings:
not specified
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Dose descriptor:
NOEL
Generation:
F1
Effect level:
250 ppm
Based on:
test mat.
Remarks:
Diuron
Sex:
male/female
Basis for effect level:
other: parental NOEL
Dose descriptor:
NOEL
Generation:
F1
Effect level:
1 750 mg/kg bw/day
Based on:
test mat.
Remarks:
Diuron
Sex:
male/female
Basis for effect level:
body weight and weight gain
Clinical signs:
no effects observed
Description (incidence and severity):
No compound-related effects were noted in pup clinical observations.
Mortality / viability:
no mortality observed
Description (incidence and severity):
No compound-related effects were noted in pup survival.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Compound-related reproductive toxicity was observed at 1750 ppm. It was manifested in pups as significantly decreased body weight in both sexes and generations.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No compound-related effects were noted in pup anomalies.
Histopathological findings:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Dose descriptor:
NOEL
Generation:
F2
Effect level:
250 ppm
Based on:
test mat.
Remarks:
Diuron
Sex:
male/female
Basis for effect level:
other: foetal NOEL
Dose descriptor:
LOEL
Generation:
F2
Effect level:
1 750 ppm
Based on:
test mat.
Remarks:
Diuron
Sex:
male/female
Basis for effect level:
body weight and weight gain
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
1 750 ppm
Treatment related:
yes
Relation to other toxic effects:
reproductive effects as a secondary non-specific consequence of other toxic effects
Dose response relationship:
yes
Relevant for humans:
yes
Conclusions:
NOEL for parental toxicity: 250 ppm Diuron
LOEL for parental toxicity: 1750 ppm Diuron
NOEL for reproductive toxicity: 250 ppm Diuron
LOEL for reproductive toxicity: 1750 ppm Diuron
Executive summary:

In a two-generation reproduction study, rats (P, 30/sex/dose) received 0, 10, 250 or 1750 ppm of read-across substance diuron in the daily diet for 73 days, and then bred within the dose groups to produce F1 litters. At weaning on Day 21, 30 F1 rats/sex/dose were randomly selected, and at least 105 days after weaning, the F1 rats were bred to produce F2 litters. For both generations, administration of the test substance continued during breeding, gestation and lactation. During premating the calculated daily intakes of diuron for both generations were as follows: for males an average of 0.68, 16.9, and 120 mg/kg/day and for females an average of 0.80, 20.3, and 144 mg/kg/day.

Compound-related parental toxicity was observed at 1750 ppm as evidenced by decreased body weight, body weight gain, and food consumption in both sexes and generations. The NOEL and LOEL for parental toxicity were 250 and 1750 ppm, respectively.

Compound-related reproductive toxicity was observed at 1750 ppm as evidenced by decreased pup body weight during the lactation period for both sexes and generations. The NOEL and LOEL for reproductive toxicity for read-across substance diuron were 250 and 1750 ppm, respectively.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
14.4 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Reliable sources
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Toxicity to reproduction: other studies

Additional information

3-generation reproductive study with Monuron

A 3-generation reproductive study was carried out with Monuron in male and female Rochester strain rats. The animals were fed 0, 125, and 2500 ppm active ingredient in the diet for 3 generations (U.S. EPA, 1975). Two litters of offspring were produced per generation. No clinical signs of toxicity or deviations from normal reproduction and lactation were observed.

At the 2500 ppm feeding level, the average size of 6 litters was slightly lower than the control group and the 125-ppm group. Ten male and 10 female weanling rats from each group of F3b generation were sacrificed. The following tissues were evaluated histologically : lung, trachea, liver, kidney, spleen, thymus, testes, ovary, epididymis, uterus, skeletal muscle, stomach, duodenum, colon, heart, brain, adrenals, eye, and bone marrow. No pathological changes were observed which could be attributable to the test material. 

Only limited details were available for Monuron, therefore the study was considered to be supportive and additional data were investigated from read-across substance Diuron, for which a 2-generation and two 1-generation reproductive toxicity studies were available.

 

Read-across with Diuron:

Two-generation study

In a two-generation reproduction study, rats (P, 30/sex/dose) received 0, 10, 250 or 1750 ppm of Diuron in the daily diet for 73 days, and then bred within the dose groups to produce F1 litters respectively (Australian Government, 2011; US EPA, 1992). At weaning on Day 21, 30 F1 rats/sex/dose were randomly selected, and at least 105 days after weaning, the F1 rats were bred to produce F2 litters. For both generations, administration of the test substance continued during breeding, gestation and lactation. During premating the calculated daily intakes of Diuron for both generations were as follows: for males an average of 0.68, 16.9, and 120 mg/kg/day and for females an average of 0.80, 20.3, and 144 mg/kg/day.

Compound-related parental toxicity was observed at 1750 ppm as evidenced by decreased body weight, body weight gain, and food consumption in both sexes and generations. The NOEL and LOEL for parental toxicity were 250 ppm (16.9-20.3 mg/kg/day) and 1750 ppm (120-144 mg/kg/day), respectively.

Compound-related reproductive toxicity was observed at 1750 ppm as evidenced by decreased pup body weight during the lactation period for both sexes and generations. The NOEL and LOEL for reproductive toxicity were 250 ppm (16.9-20.3 mg/kg/day) and 1750 ppm (120-144 mg/kg/day).

Taking into account the molecular weight differences between Diuron (233.097 g/mol) and Monuron (198.6519), a conversion factor is applied to the parental and reproductive NOAEL of 250 ppm corresponding to lowest value of 16.9 mg/kg bw, leading to a ‘target NOAEL’ of 0.85 x 16.9 mg/kg/day = 14.4 mg/kg bw.

 

Other reproductive studies

A supporting one-generation reproductive toxicity was conducted with Diuron in adult male rats. Diuron was diluted in corn oil and administered by oral gavage to groups of 18–20 rats at doses of 0, 125 or 250 mg/kg per day for 30 days; the control group received only the corn oil vehicle(Fernandes et al., 2007). At the end of the treatment period, approximately half the animals from each group were assigned to one of two terminal assessment lines: (1) reproductive organ, liver and kidney weights; measurement of Duron concentrations in liver and kidney; plasma testosterone determinations; evaluation of daily sperm production per testis; sperm number and sperm transit time in the epididymis; or (2) sexual behavior assessment during cohabitation with a receptive female; fertility and pregnancy outcome after natural mating; testicular, epididymal, kidney and liver histopathology; sperm morphology. After 30 days of oral Diuron treatment, there were no treatment-related changes in body weights, but dose-related Diuron residues were detected in the liver of all treated rats and absolute and relative liver weights were increased in both groups. There were no statistically significant differences between the treated and control groups obtained in plasma testosterone concentrations, or in parameters of daily sperm production, sperm reserves in the epididymis, sperm morphology or measured components of male sexual behavior.

Another supporting reproductive toxicity study was conducted with Diuron in pregnant rats via the diet at 500 or 750 ppm from gestational day 12 (GD 12) until the end of lactation period (postnatal day 21, PND 21) (Fernandes et al., 2012). After weaning male offspring received basal diet or diet containing Diuron until PND 42 (peripubertal age). At PND 90, adult male rats from each experimental group were anesthetized and euthanized for evaluation of body and reproductive organ weights, sperm parameters, plasma testosterone levels, and testicular and epididymal histopathology. Male offspring exposed to Diuron at 750 ppm displayed reduced body weight at PND 10, 21, 42, and 90 compared to controls. At PND 90, diuron treatment did not induce significant change in daily sperm production, sperm morphology and motility, and testosterone levels compared to controls. In conclusion, Diuron at 750 ppm induced male offspring toxicity but these alterations were not permanent, as evidenced by absence of reproductive-system alterations in adult Sprague Dawley rats.

Mode of Action Analysis / Human Relevance Framework

Reproductive findings were limited to lower pup body weights, and they were only seen at a parental toxic dose level, therefore they were considered secondary non-specific effects, not relevant for humans.

Justification for classification or non-classification

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 reproductive toxicity.