Dimethyl octadecylphosphonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Remarks:

other: combined repeated dose and reproductive/developmental toxicity screening test

Type of information:

experimental study

Adequacy of study:

key study

Study period:

July 2012 to March 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 11 weeks
- Weight at study initiation: Males weighed ca. 292 to 299 g (mean group weights), females weighed ca. 201 to 204 g (mean group weights)
- Fasting period before study: No
- Housing: Housed in groups of 5 with the exception of the mating period when 1 female was housed with 1 male and post mating when females were housed individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 40-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 02 September 2012 to 01 November 2012

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on exposure:

VEHICLE
- Justification for use and choice of vehicle (if other than water): based on trial formulations at Wil Research Europe
- Concentration in vehicle: 20, 60 and 200 mg/g nominal
- Amount of vehicle (if gavage): 5 ml/kg body weight

Details on mating procedure:

Following a minimum of 21 days of exposure for the males and females, one female was cohabitated with one male of the same treatment group,
avoiding sibling mating (Macrolon plastic cage). Detection of mating was confirmed by evidence of sperm in the vaginal lavage or by the appearance of an intravaginal copulatory plug. This day was designated Day 0 post-coitum. Once mating occurred, the males and females were separated. A maximum of 14 days was allowed for mating, after which females who had not shown evidence of mating were separated from their males.
Detection of mating was not confirmed for animal no. 53 which did deliver live offspring. The mating date of this animal was estimated at 21 days prior to the actual delivery date. This day was designated Day 0 postcoitum.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analysis performed on samples prepared for use on 03 September 2012. No test substance was found in the Group 1 formulations (control group). The concentrations analysed in the formulations of Group 2, 3 and 4 were in agreement with target concentrations (i.e. mean accuracies between 90% and 110%).
The formulations of Group 2 and 4 were homogeneous (i.e. coefficient of variation ≤ 10%). Group 3 was not tested for homogeneity.
Formulations at the entire range were stable when stored at room temperature under normal laboratory light conditions for at least 5 hours (i.e. relative difference ≤ 10%).
The long term storage samples were stable at ≤-70°C for at least 12 days.

Duration of treatment / exposure:

Treatment: daily oral gavage dosing
Males were exposed for 36 days, i.e. 3 weeks prior to mating, during mating, and up to the day prior to scheduled necropsy. Females were exposed for 47-60 days, i.e. during 3 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation (up to the day prior to scheduled necropsy).
Pups were not treated directly but were potentially exposed to the test substance in utero and through lactational transfer.

Frequency of treatment:

Once daily

Details on study schedule:

- F0 parental animals were mated after a minimum of 21 days exposure and 14 days was allowed for mating. The females were allowed to litter normally. Day 1 of lactation was defined as the day when a litter was found completed (i.e. membranes and placentas cleaned up, nest build up and/or feeding of pups started). Females that were littering were left undisturbed.

Study schedule:
Start treatment: 02 September 2012
Start mating: 23 September 2012
Blood sampling: 08 October 2012 (selected males), 19, 22-24 October 2012 (selected females)
Delivery of litters: 14-18, 26 and 27 October 2012
Necropsy: 8 October 2012 (selected males), 19, 22-24 October and 01 November 2012 (selected females)
Experimental completion date: 01 November 2012 (end of in-life phase)

Remarks:

Doses / Concentrations:
0
Basis:
other: mg/kg body weight/day

Remarks:

Doses / Concentrations:
100
Basis:
other: mg/kg body weight/day

Remarks:

Doses / Concentrations:
300
Basis:
other: mg/kg body weight/day

Remarks:

Doses / Concentrations:
1000/600
Basis:
other: mg/kg body weight/day

No. of animals per sex per dose:

10 males and 10 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose levels were selected based on results of a 10-day dose ranging finding study
- Rationale for animal assignment (if not random): random assignment
- Rationale for selecting satellite groups: not selected.
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random):

Parental animals: Observations and examinations:

General repeat dose toxicity study observations include: Mortality/viability, clinical signs (daily within the cage and weekly with animal outside of the cage), functional observations, body weights, food consumption, visual assessment of water consumption, haematology, clinical chemistry, necropsy examination, organ weight collection and histopathology of a full range of protocol listed tissues. Testes from the 5 males selected for histological examination in the control and high dose group and from any males suspected of being infertile was also processed to allow staging of spermatogenesis.

General reproductive data:
Male number paired with, mating date, confirmation of pregnancy, and delivery day were recorded.
Pregnant females were examined to detect signs of difficult or prolonged parturition, and cage debris of pregnant females was examined to detect signs of abortion or premature birth. Any deficiencies in maternal care (such as inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups or apparently inadequate lactation or feeding) were examined.

Oestrous cyclicity (parental animals):

Not specifically investigated.

Sperm parameters (parental animals):

Not examined

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
- If yes, maximum of [...] pups/litter ([...]/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain (pups weighed on days 1 and 4 of lactation)

GROSS EXAMINATION OF DEAD PUPS: Pups surviving to planned terminated were killed by decapitation on Days 5-7 of lactation. All pups were sexed and descriptions of all external abnormalities were recorded. The stomach for pups not surviving to the scheduled necropsy date was examined for the presence of milk. If possible, defects or cause of death were evaluated.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals were examined macroscopically following completion of the mating period (a minimum of 28 days dose administration)
- Maternal animals - Day of necropsy: Females which delivered: lactation days 5-7, female which failed to deliver: post coitum days 25-26 (females with evidence of mating), females with total litter loss: within 3 days of litter loss.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal tissues and organs with special attention paid to reproductive organs.
The numbers of former implantation sites and corpora lutea were recorded for all paired females. In case no macroscopically visible implantation sites were present, nongravid uteri were stained using the Salewski technique (Ref. 1) in order to detect any former implantation sites (Salewski staining prepared at WIL Research Europe using Ammoniumsulfide-solution 20% (Merck, Darmstadt, Germany) and Milli-Ro water (Millipore Corporation, Bedford, USA)).

HISTOPATHOLOGY / ORGAN WEIGHTS
A full range of tissues and organs were collected and preaserved in formalin. this is also described in detail in IUCLID summary 7.5.1. Organs were weighed from 5/sex and included the following reproductive organs: testes, epididymides, prostate, seminal vesicles including coagulating glands, ovaries and uterus (including cervix). In the remaining males testes and epididymides were weighed. Tissues and organs associated with reproductive/developmental toxicity screen are tabulated in Table 1.

Postmortem examinations (offspring):

Pups surviving to planned termination were killed by decapitation on Days 5-7 of lactation.

All pups were sexed and descriptions of all external abnormalities were recorded. The stomach for pups not surviving to the scheduled necropsy date was examined for the presence of milk. If possible, defects or cause of death were evaluated.

Statistics:

The following statistical methods were used to analyze the data:
– If the variables could be assumed to follow a normal distribution, the Dunnett-test (Ref. 2; many- to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
– The Steel-test (Ref. 3; many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
– The Fisher Exact-test (Ref. 4) was applied to frequency data.
– The Kruskal-Wallis nonparametric ANOVA test (Ref. 5) was applied to motor activity data.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores).

Reproductive indices:

the following calculations were performed:
Mating index (%); number of females mated/number of females paired x 100
Fertility index (%); number of pregnant females/number of females paired x100
Conception index (%); number of pregnant females/number of females mated x100
Gestation index (%); number of females bearing live pups/number of pregnant females x100
Duration of gestation; number of days between confirmation of mating and the beginning of parturition

Offspring viability indices:

Percentage of live males at first litter check; number of live male pups at first litter check/number of live pups at first litter check x100
Percentage of live females at first litter check; number of live female pups at first litter check/ number of live pups at first litter check x100
Percentage of postnatal loss; number of dead pups before planned necropsy/number of live pups at first litter check x100
Viability index; number of live pups before planned necropsy/number of pups born live

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Hunched posture, piloerection, diarrhoea, salivation, lethargy, lean appearance recorded at 1000 mg/kg. Resolution of these symptoms noted after dose level reduced to 600 mg/kg.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Weight loss and lower food intake recorded at 1000 mg/kg. After reducing the dose to 600 mg/kg the animals' food intake increased and they regained body weight but remained lighter than controls.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Weight loss and lower food intake recorded at 1000 mg/kg. After reducing the dose to 600 mg/kg the animals' food intake increased and they regained body weight but remained lighter than controls.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Stomach - local iritation noted - all treated groups. Mesenteric lymph nodes congestion/sinus histiocytosis at 600 mg/kg, Adrenals vacuolation zona glomerulosa 600 mg/kg

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

Animals mated on a 1 male to 1 female basis without specific oestrus cycle monitoring.

Reproductive function: sperm measures:

not examined

Description (incidence and severity):

no specific sperm measures performed.

Reproductive performance:

no effects observed

Description (incidence and severity):

Mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites were unaffected by treatment.

Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all selected animals. There was a variation in motor activity; this did not indicate a relationship with treatment. All groups showed a similar habituation profile with very high activity in the first interval that decreased over the duration of the test period.

No toxicologically relevant effects on reproductive parameters were noted. The mating, fertility and conception indices, precoital time, and number of corpora lutea and implantation sites were unaffected by treatment. The spermatogenic staging profiles were normal for all examined males. No abnormalities were seen in the reproductive organs of the rats who failed to sire or deliver healthy pups, which could account for their infertility.

No toxicologically relevant effects on the gestation index and duration, parturition, maternal care and early postnatal pup development (mortality, clinical signs, body weight and macroscopy) were observed.
Gestation
The gestation index and duration of gestation were unaffected by treatment. There were 9, 10, 9 and 10 pregnant females in the control, 100, 300 and 600 mg/kg groups, respectively. The gestation index was 88.9, 90, 100, and 100% for these groups.

Parturition/maternal care
No signs of difficult or prolonged parturition were noted among the pregnant females.
Examination of cage debris of pregnant females revealed no signs of abortion or premature birth and no deficiencies in maternal care were observed.

Dose descriptor:

NOAEL

Remarks:

reproduction

Effect level:

> 600 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Dose descriptor:

NOAEL

Remarks:

developmental

Effect level:

> 600 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Clinical signs:

no effects observed

Description (incidence and severity):

No treatment related findings

Mortality / viability:

no mortality observed

Description (incidence and severity):

No treatment related effect on number of dead and living pups at the first litter check, postnatal loss, viability index and sex ratio recorded.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No teatment related findings

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 treatment related findings

Histopathological findings:

not examined

Early postnatal pup development
Number of dead and living pups at first litter check, postnatal loss, viability index and sex ratio were unaffected by treatment, and clinical signs, body weight and external macroscopy did not reveal treatment-related findings.

Mortality
One, two and two pups in the 100, 300 and 600 mg/kg groups, respectively, died or went missing in the first days of lactation. No pups died in the control group. One female at 600 mg/kg (no. 72) had a total litter loss after her single pup went missing. This pup was most likely cannibalized. No toxicological relevance was attributed to these dead/missing pups since the mortality incidence did not show a dose-related trend and remained within the range considered normal for pups of this age.

Clinical signs
Scab/scabs on the head were noted for two pups at 300 mg/kg. Abnormal posture of the right hind leg was recorded for one pup at 600 mg/kg. These were the only clinical sign noted and were considered incidental in nature.

Body weights
Body weights of pups were unaffected by treatment up to 600 mg/kg.

Macroscopy
The only macroscopic findings that were noted were considered to be incidental in nature.

Reproductive effects observed:

not specified

REPRODUCTION DATA SUMMARY

	Group 1 Control	Group 2 100 mg/kg	Group 3 300 mg/kg	Group 4 600 mg/kg
Females paired	10	10	10	10
Females mated	10	10	10	10
Females pregnant	9	10	9	10
Non-pregnant females	1	0	0	0
Females with living pups on Day1	8	9	9	10
Mating index(%) (Females mated /Females paired) *100	100.0	100.0	100.0	100.0
Fertility index(%) (Pregnant females/Females paired) *100	90.0	100.0	90.0	100.0
Conception index(%) (Pregnant females/Females mated) *100	90.0	100.0	90.0	100.0
Gestation index(%) (Females with living pups on Day1 /Pregnant females) *100	88.9	90.0	100.0	100.0

 

 

Precoital time: F0-Generation – Post coitum

DAYOFTHE PAIRINGPERIOD	GROUP1 CONTROL	GROUP2 100MG/KG	GROUP3 300MG/KG	GROUP4 600MG/KG
NUMBER OF FEMALES MATED
1	3	3	4	3
2	1	2	1	5
3	3	3	4	2
4	2	−	1	−
11	−	1	−	−
12	−	1	−	−
13	1	−	−	−
MEDIAN PRECOITAL TIME	3	3	3	2
MEAN PRECOITAL TIME	3.5	3.9	2.2	1.9
N	10	10	10	10

 Not significant by Steel-test

Corpora lutea and implantation sites summary

		Group 1 Control	Group 2 100 mg/kg	Group 3 300 mg/kg	Group 4 600 mg/kg
NECROPSY CorporaLutea	MEAN	15.2	13.0	13.8	10.6
	ST.DEV	5.0	6.1	5.5	3.4
	N	9	10	9	10
Implantations	MEAN	11.6	8.7	11.1	9.8
	ST.DEV	3.0	4.8	3.0	3.4
	N	9	10	9	10

 not significant by Steel test

 Developmental data – F0-Generation – Lactation

	Group 1 Control	Group 2 100 mg/kg	Group 3 300 mg/kg	Group 4 600 mg/kg
LITTERS - TOTAL	8	9	9	10
DURATION OF GESTATION
MEAN(+)	20.9	21.4	21.2	21.1
ST.DEV.	0.8	0.7	0.4	0.3
N	8	9	9	10
DEAD PUPS AT FIRST LITTER CHECK
LITTERS AFFECTED (#)	0	1	0	0
TOTAL	0	1	0	0
MEAN (+)	0.0	0.1	0.0	0.0
ST. DEC.	0.0	0.3	0.0	0.0
N	8	9	9	10
LIVING PUPS AT FIRST LITTER CHECK
% OF MALES / FEMALES (#)	52/ 48	54/ 46	49/ 51	59/ 41
TOTAL	87	80	102	93
MEAN(+)	10.9	8.9	11.3	9.3
ST.DEV.	3.2	3.6	3.3	3.6
N	8	9	9	10
POSTNATAL LOSS
% OF LIVING PUPS	0.0	0.0	2.0	2.2
LITTERS AFFECTED(#)	0	0	2	2
TOTAL(#)	0	0	2	2
MEAN(+)	0.0	0.0	0.2	0.2
ST.DEV.	0.0	0.0	0.4	0.4
N	8	9	9	10
VIABILITY INDEX(#)	100.0	100.0	98.0	97.8

Viability index= (Number of alive pups before planned necropsy/ Number of pups born alive)*100

+/++Steels test significant at 5% (+) or 1% (++) level

#/##Fisher's Exact test significant at 5% (#) or 1% (##) level

 

BODY WEIGHTS OF PUPS (G) F0-GENERATION - LACTATION

Day	Sex		Group 1 Control	Group 2 100 mg/kg	Group 3 300 mg/kg	Group 4 600 mg/kg
1	M	MEAN	6.3	6.9	6.5	6.1
		ST.DEV.	0.8	1.1	0.8	0.5
		N	8	9	9	9
	F	MEAN	6.1	6.5	6.3	5.7
		ST.DEV.	0.7	0.9	0.7	0.5
		N	8	9	9	10
	M+F	MEAN	6.2	6.8	6.4	5.9
		ST.DEV.	0.7	1.0	0.7	0.5
		N	8	9	9	10
4	M	MEAN	9.6	10.5	9.4	9.0
		ST.DEV.	1.5	2.2	1.2	0.9
		N	8	9	9	9
	F	MEAN	9.3	9.9	9.3	8.6
		ST.DEV.	1.3	1.7	1.0	0.8
		N	8	9	9	9
	M+F	MEAN	9.5	10.3	9.4	8.8
		ST.DEV.	1.4	2.0	1.1	0.8
		N	8	9	9	9

 Not significant by Dunnett's test

Conclusions:

In conclusion, treatment with Dimethyl octadecylphosphonate (DMOP) by oral gavage in male and female Wistar Han rats at dose levels of 100, 300, 600 and 1000 mg/kg body weight/day revealed parental toxicity at 600 mg/kg body weight/day. No reproduction and developmental toxicity was observed for treatment up to 600 mg/kg body weight/day.

Based on these results, the following No Observed Adverse Effect Level (NOAEL) was derived:
Reproduction: at least 600 mg/kg bw/day
Developmental: at least 600 mg/kg bw/day

Executive summary:

Dimethyl octadecylphosphonate (DMOP) was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 0, 100, 300 and 1000 (Days 1-13 of treatment) mg/kg. Due to toxicity observed at 1000 mg/kg, the dose level of Group 4 was lowered to 600 mg/kg from Day 14 of treatment onwards. Males were exposed for 36 days, i.e. 3 weeks prior to mating, during mating, and up to termination. Females were exposed for 47-60 days, i.e. during 3 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation. Pups were not treated directly but were exposed to the test substance in utero and through lactational transfer.

Formulation analysis showed that the formulations were prepared accurately, were homogenous, and were stable for at least 5 hours at room temperature.

General reproductive data for the parenteral animals was recorded. This included male number paired with, mating data, confirmation of pregnancy and delivery date. Pregnant females were examined to detect signs of difficult or prolonged parturition and cage debris of pregnant females was examined top detect signs of abortion or premature birth. Any deficiencies in maternal care (such as inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups or apparently inadequate lactation or feeding) were examined.

Each litter of pups was examined for mortality and viability. The numbers of live and dead pups on Day 1 of lactation and daily thereafter was determined and if possible, cause of death was evaluated. Clinical signs examinations were performed at least once daily. On lactation days 1 and 4 the pups were weighed and their sex determined. The pups were sacrificed on Days 5 to 7 of lactation. Sex was confirmed and descriptions of any external abnormalities recorded. The stomach of any pup not surviving to the scheduled termination was examined for the presence of milk and cause of death established if possible.

The following indices were calculated: mating index, fertility index, conception index, gestation index, duration of gestion, percentage of live males at first litter check, percentage of live females at first litter check, percentage of postnatal loss, viability index.

No toxicologically relevant effects on reproductive parameters such as mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites. The spermatogenic staging profiles were normal for all examined males. No abnormalities were seen in the reproductive organs of the rats who failed to sire or deliver healthy pups, which could account for their infertility. For developmental data, no toxicologically relevant effects on gestation index and duration, parturition, maternal care and early postnatal pup development (mortality, clinical signs, body weight and macroscopy) were observed. It was concluded that based on these results the NOAEL for reproductive and developmental effects was at least 600 mg/kg bw/day.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Additional information

In a GLP, OECD 422 compliant combined 28-day repeated dose toxicity study with the reproduction /developmental toxicity screening test, dimethyl octadecylphosphonate (DMOP) was administered by daily oral gavage to groups of 10 male and 10 female Wistar Han rats at dose levels of 0, 100, 300 and 1000 (Days 1-13 of treatment) mg/kg. Due to toxicity observed at 1000 mg/kg, the dose level of Group 4 was lowered to 600 mg/kg from Day 14 of treatment onwards. Males were exposed for 36 days, i.e. 3 weeks prior to mating, during mating, and up to termination. Females were exposed for 47-60 days, i.e. during 3 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation. Pups were not treated directly but were exposed to the test substance in utero and through lactational transfer before sacrifice on days 5 to 7 of lactation.

General reproductive data for the parenteral animals was recorded whilst sex ratio, viability, growth and external abnormalities of the pups was reported. The stomach of any pup not surviving to the scheduled termination was examined for the presence of milk and cause of death established if possible. The following indices were calculated: mating index, fertility index, conception index, gestation index, duration of gestation, percentage of live males at first litter check, percentage of live females at first litter check, percentage of postnatal loss, viability index.

No toxicologically relevant effects on reproductive parameters such as mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites. The spermatogenic staging profiles were normal for all examined males. No abnormalities were seen in the reproductive organs of the rats who failed to sire or deliver healthy pups, which could account for their infertility. It was concluded that based on these results the NOAEL for reproductive effects was at least 600 mg/kg bw/day.

Justification for selection of Effect on fertility via oral route:
Key study

Effects on developmental toxicity

Additional information

In a GLP, OECD 422 compliant combined 28-day repeated dose toxicity study with the reproduction /developmental toxicity screening test, dimethyl octadecylphosphonate (DMOP) was administered by daily oral gavage to groups of 10 male and 10 female Wistar Han rats at dose levels of 0, 100, 300 and 1000 (Days 1-13 of treatment) mg/kg. Due to toxicity observed at 1000 mg/kg, the dose level of Group 4 was lowered to 600 mg/kg from Day 14 of treatment onwards. Males were exposed for 36 days, i.e. 3 weeks prior to mating, during mating, and up to termination. Females were exposed for 47-60 days, i.e. during 3 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation. Pups were not treated directly but were exposed to the test substance in utero and through lactational transfer before sacrifice on days 5 to 7 of lactation.

General reproductive data for the parenteral animals was recorded whilst sex ratio, viability, growth and external abnormalities of the pups was reported. The stomach of any pup not surviving to the scheduled termination was examined for the presence of milk and cause of death established if possible. The following indices were calculated: mating index, fertility index, conception index, gestation index, duration of gestation, percentage of live males at first litter check, percentage of live females at first litter check, percentage of postnatal loss, viability index.

No toxicologically relevant effects on gestation index and duration, parturition, maternal care and early postnatal pup development (mortality, clinical signs, body weight and macroscopy) were observed. It was concluded that based on these results the NOAEL for developmental effects was at least 600 mg/kg bw/day.

Justification for classification or non-classification

Overall, the data obtained from the OECD422 reproductive and developmental toxicity screening test did not identify an effect on fertility, reproductive performance, development and viability of the offspring overs days 1 to 5 of lactation at dose levels up to and including 600 mg/kg bw/day. Therefore, it is considered that DMOP should not be classified for reproduction toxicity.