O,O-bis(methylphenyl) hydrogen dithiophosphate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

OECD 422, rat, oral, NOAEL 182.8 mg/kg bw/day

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2012

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Research, Models and Services Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld
- Age at study initiation: 59 days
- Weight at study initiation: Males: 319.0 g to 353.1 g, Females: 209.8 g to 248.4 g

- Fasting period before study:
- Housing: singly (With the exception of the mating period) in MAKROLON cages (type III plus) with a basal surface of approx. 39 cm x 23 cm and a height of approx. 18 cm
- Diet (e.g. ad libitum): ssniff R-Z V1324 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany) . The food was offered ad libitum with the exception of the night before the day of blood withdrawal for laboratory examination
- Water (e.g. ad libitum): Tap water was offered ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C
- Humidity (%): of 55% ± 15%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 h d / 12 h l

IN-LIFE DATES: From: Males and females : September 5th 2012 To: Males:October 17, 2012 Females:November 3, 2012

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): The test item formulations were freshly prepared on each administration day.
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: Variable, The dose of the test item was adjusted to the animal's actual body weight daily.
- Amount of vehicle (if gavage): 10 mL/kg b.w./day
- Lot/batch no. (if required): Batch no.: 11078709, Caesar & Loretz GmbH, 40721 Hilden, Germany.
- Purity:

Details on mating procedure:

Sexually mature male and female rats were randomly paired for mating. Mating was monogamous: 1 male and 1 female animal were placed in one cage during the dark period. The female was placed with the same male until pregnancy had occurred or 2 weeks had elapsed. Each morning the females were examined for the presence of sperm or a vaginal plug. If findings were negative, mating was repeated. The day of conception (day 0 of gestation) was considered to be the day on which sperm was found. In case pairing was unsuccessful, re-mating of females with proven males of the same group was considered. This procedure was repeated until at least 8 pregnant dams were available for each group.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

For the analysis of the test item-vehicle mixtures samples of approx. 2 x 1 mL
were taken at the following time points and stored at ≤ minus 20°C until analysis
at LPT:
Start of treatment period Concentration and stability
Immediately after preparation of the test item vehicle
mixtures as well as 8 and 24 hours after
storage of the test item preparations at room
temperature:
3 samples/dose level group (groups 2 to 4)
Number of samples: 3 x 4 = 12
Homogeneity
At start of administration, during (middle) administration
and before administration to the
last animal of each dose level group:
3 samples/dose level group (groups 2 to 4).
Number of samples: 3 x 4 = 12
End of treatment period Concentration
During treatment with the test item always before
administration to the last animal/dose level
group:
1 sample/dose level group (groups 2 to 4).
Number of samples: TD 28 (1 x 3) = 3
Number of samples: TD 41 (1 x 3) = 3
Sum of all samples: 30
Sum of all aliquots: 60
The samples were labelled with the study number, test item, test species, type of
sample, aliquot number, concentration, test day, sampling time and date.

Duration of treatment / exposure:

Males
The daily administration of the test item started
two weeks before mating and lasted until the
day before sacrifice (considering a minimum total
dosing period of at least 28 days).
Females
The daily administration of the test item started
two weeks before mating and lasted up to at
least day 3 of lactation.

Frequency of treatment:

once daily

Remarks:

Doses / Concentrations:
0 mg/kg bodyweight/day
Basis:
actual ingested

Remarks:

Doses / Concentrations:
13.7 mg/kg bodyweight/day
Basis:
actual ingested

Remarks:

Doses / Concentrations:
45.7 mg/kg bodyweight/day
Basis:
actual ingested

Remarks:

Doses / Concentrations:
137.1/182.8 mg/kg bodyweight/day
Basis:
other: actual ingested, The high dose level was increased from 137.1 mg/kg to 182.8 mg/kg on test day 18, because the effects observed with 137.1 mg/kg after 2 weeks appeared to be too slight.

No. of animals per sex per dose:

80 animals (40 male and 40 female rats),
10 animals/sex/group.
A sufficient number to grant at least 8 pregnant
females per group for evaluation of the F0 generation

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: See supporting study: 14-DAY DOSE-RANGE-FINDING STUDY OF CRESYL-P1 (DANAFLOATTM 070) BY ORAL ADMINISTRATION TO RATS

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least daily, The frequency was increased when signs of toxicity were observed.
Cageside observations included skin/fur, eyes, mucous membranes, respiratory
and circulatory systems, somatomotor activity and behaviour patterns. The
onset, intensity and duration of any signs observed were recorded.
Individual animals were observed before and after dosing at each time of dosing for
any signs of behavioural changes, reaction to treatment or illness.
In addition, animals were checked regularly throughout the working day from 7:00
a.m. to 3:45 p.m. On Saturdays and Sundays animals were checked regularly from
7:00 a.m. to 11:00 a.m. with a final check performed at approximately 3:30 p.m.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least daily, The frequency was increased when signs of toxicity were observed.
Additionally, once before the first exposure (to allow within-subject comparisons)
and once a week thereafter, detailed clinical observations were made in all animals
outside the home cage in a standard arena and at the same time, each time preferably
by observers unaware of the treatment. Signs noted included changes in
skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and
autonomic activity (e.g. lacrimation, piloerection, pupil size, and unusual respiratory
pattern). Changes in gait, posture and response to handling as well as the
presence of clonic or tonic movements, stereotypies (e.g. excessive grooming,
repetitive circling), difficult or prolonged parturition or bizarre behaviour (e.g. selfmutilation,
walking backwards) were also recorded.
Dated and signed records of appearance, change, and disappearance of clinical
signs were maintained on clinical history sheets for individual animals.
BODY WEIGHT: Yes / No / No data
- Time schedule for examinations:

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes / No / No data
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: Yes / No / No data
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.

URINALYSIS: Yes / No / No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

Dose descriptor:

NOAEL

Remarks:

(Effects on the F0-generation)

Effect level:

ca. 45.7 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: Effects on the F0-generation

Dose descriptor:

NOAEL

Remarks:

(Reproductive toxicity)

Effect level:

> 182.8 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: Effects on reproductive toxicity. The high dose level was increased from 137.1 mg/kg to 182.8 mg/kg on test day 18, because the effects observed with 137.1 mg/kg after 2 weeks appeared to be too slight

Dose descriptor:

NOAEL

Remarks:

(Effects on the development of the F1 offspring )

Generation:

F1

Effect level:

ca. 45.7 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Reproductive effects observed:

not specified

Conclusions:

Based on this study it appears that Cresyl-P1 is not a reproductive or a developmental toxicant at exposure levels below those also toxic for the parental generation

Executive summary:

The registered substance has been tested in an Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test according to OECD Guideline 422 and under GLP following an 14-Day Dose Range Finder Study. Based on this study it appears that Cresyl-P1 is not a reproductive or a developmental toxicant at exposure levels below those also toxic for the parental generation.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

182.8 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

High quality, guideline study

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the findings of the Developmental screening study Cresyl-P1 is not a reproductive or a developmental toxicant and no classification is warranted accoring to Regulation (EC) No 1272/2008.