Octyl (R)-2-(4-chloro-2-methylphenoxy)propionate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: original study report not available, but secondary source contains sufficient data to assess study at least as rel. 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Wistar rats 35 days old

Route of administration:

oral: feed

Vehicle:

other: fed in diet

Details on mating procedure:

- M/F ratio per cage: 1:1 ratio.
If an animal of the F0 or F1 generation parental animals had not produced any offspring these animals were mated again with control animals to assess their fertility.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

whole lifetime (F0 generation), during which two matings and rearings of offspring took place

Frequency of treatment:

fed in diet, continuously

Details on study schedule:

At least 70 days after the beginning of treatment the animals were allowed to mate in a 1:1 ratio. Females were allowed to litter and rear their pups (F1a generation pups) until either day 4, when the pups were culled to 8 pups/litter preferably with 4 males and four females/litter or day 21 after parturition. At least 10 days after the last weaning of the F1a generation pups, the F0 parental animals were mated again in a ratio of 1:1 for the F1b generation and the females were allowed to rear their pups as the F1a generation. After the F1b generation had been weaned, the F0 generation was fasted for 16 hours before sacrifice.
After weaning the F1a pups were used to establish the F2 generation by choosing 25 males and 25 females from each dose group with all litters being represented if possible. The F1a generation received the test substance at the same concentration as their parents, and at least 98 days after formation of the F1 generation parental animals, the males and females were mated at a ratio of 1:1 avoiding mating of siblings. Females were allowed to litter (F2 pups) and at day 4 after parturition culling to 8 pups/female was carried out. After the F2 pups had been weaned the F1 generation was fasted for 16 hours before sacrifice.
All pups, which were not used for establishing the next generation, were sacrificed after weaning.

Remarks:

Doses / Concentrations:
0, 20, 100 and 500 ppm Mecoprop (racemic)
Basis:
nominal in diet

No. of animals per sex per dose:

25

Control animals:

yes, plain diet

Parental animals: Observations and examinations:

Food consumption and body weight were determined at the requested intervals with few minor exceptions. Clinical observations were carried out daily. Before sacrifice of parental animals urine and blood were collected and analyzed.

Oestrous cyclicity (parental animals):

Male and female reproduction data were calculated using relevant data and formulas.

Sperm parameters (parental animals):

Male and female reproduction data were calculated using relevant data and formulas.

Litter observations:

Pup development data were calculated using relevant data and formulas.
The following developmental and behaviourial tests were carried out: 1) pinna unfolding, 2) opening of the auditory canal, 3) opening of the eyes, 4) gripping reflex on day 13, hearing test on day 21, and pupillary reflex on day 29.

Postmortem examinations (parental animals):

Parental animals of the F0 and F1 generations were subjected to gross pathology after weighing of animals, liver, kidneys, and testes, and after fixation of 13 organs these were all subjected to a histopathological examination in all animals from the control and 500 ppm groups. In addition livers, kidneys, and gross lesions in the 20 and 100 ppm groups were studied likewise.

Cited from Mecoprop-P, EU Review Programme on active substances in Plant Protection Products, Scientific Evaluation and Assessment, The Danish Environmental Protection Agency, Draft December 1998 (Volume 3, Annex B) and Addendum II July 2002:
"There were no substance-related differences in food consumption and body weight."
"In the F0 males and females there were no treatment-related differences in mating and fertility indices for the F1a and F1b generations."
"There were no substance related differences in food consumption and body weight gains in the F1 males and females during the whole study period, including gestation and lactation periods of the dams of the F2 pups.
In clinical chemistry, urinanalyses, and pathology no substance related changes were observed in the F0 and F1 parental animals except for increased absolute and relative kidney weights of both sexes and generations in the 500 ppm group and in the F0 males and both sexes of the F1 generation."

Dose descriptor:

other: NOAEL for maternal toxicity

Effect level:

100 other: ppm (corresponding to 10 mg/kg bw and day)

Sex:

female

Basis for effect level:

other: Kidney weights were affected at next higher dose level (500 ppm)

Remarks on result:

other: Generation not specified (migrated information)

Dose descriptor:

other: NOAEL for fetal toxicity

Effect level:

100 other: ppm (corresponding to 10 mg/kg bw and day)

Sex:

male/female

Basis for effect level:

other: Increased pub death and decreased pub body weight gain at next higher dose level (500 ppm)

Remarks on result:

other: Generation not specified (migrated information)

Cited from Mecoprop-P, EU Review Programme on active substances in Plant Protection Products, Scientific Evaluation and Assessment, The Danish Environmental Protection Agency, Draft December 1998 (Volume 3, Annex B) and Addendum II July 2002:
"There were no treatment-related differences in F1a and F1b pup numbers and status at delivery. The number of pups, which died or were cannibalized from day 1 to day 4 post partum (before culling), was statistically increased in the F1a 500 ppm group (p<0.01). Also in the F2 pups the number of dead pups on day 1 was significantly increased (p<0.01) in the 500 ppm group." For a summary of these findings see table below.
"As a consequence of the increased pup death from day 1 to 4 post partum in the F1a pups of the 500 ppm group the viability index of this group was significantly (p<0.01) reduced. The lactation index, an indicator of pup survival from day 4 to 21 post partum, was not influenced by administration of the test substance, nor was the sex ratio affected. The body weight gain of pups of the 500 ppm F1a group was significantly (p<0.05) reduced. In the F2 500 ppm pups body weight gain from day 4 to 7 and day 7 to 14 was significantly (p<0.05) reduced in males and in males and females combined. This resulted in a significant (p<0.05) reduction in body weight gain from day from day 4 to 21 in both males and females separately and in both sexes combined.
In the developmental and behaviourial tests the F1b pups had delayed pinna unfolding (p<0.01) in the 100 and 500 ppm groups. In the F2 pups pinna unfolding was delayed in the 20, 100, and 500 ppm groups (p<0.01), and auditory canal opening was delayed (p<0.01) in the 500 ppm group.
At pup necropsy no substance related findings were observed in F1a, F1b, and F2 pups."

Reproductive effects observed:

not specified

Number of dead pups day 0-4 in the generation study with Mecoprop

Litter type	Sum dead pups day 4 (dead day 0 + dead day 1-4)
	0 ppm	20 ppm	100 ppm	500 ppm
F1a	8(1+7)	6(0+6)	15(2+13)	23(3+20^##)
F1b	5(1+4)	8(1+7)	13(4+9)	17(6+11)
F2	17(1+16)	22(2+20)	22(0+22)	32(13^##+19)

 ^# significance level 0.05, ^## significance level 0.01

Executive summary:

A two-generation reproduction toxicity study according to OECD TG 416 was conducted with Mecoprop (racemic). Groups of 25 male and female Wistar rats were given 0, 20, 100, or 500 ppm test substance in the diet for their whole lifetime (F0 generation), during which two matings and rearings of offspring took place.

For summary and assessment of findings see citation below.

 

Cited from Mecoprop-P, EU Review Programme on active substances in Plant Protection Products, Scientific Evaluation and Assessment, The Danish Environmental Protection Agency, Draft December 1998 (Volume 3, Annex B) and Addendum II July 2002:

"The study has been carried out well according to OECD guideline 416 and GLP. The test report considers a NOAEL of 500 ppm for adult “fertility”. However, the rapporteur considers 100 ppm as the NOAEL for the overall reproductive function as significant decreases were seen at the 500 ppm dose level for pup viability day 0-4 post partum, for pinna unfolding and for body weight gain during lactation in at least two of the three tested breeds. A general NOAEL for systemic toxicity is 100 ppm as absolute and relative kidney weights were affected in the 500 ppm groups. The increased pup death observed is not substance related, as the affected litters were large in number of pups, and the decrease in pup weight gain during lactation is most likely caused by maternal toxicity."

And further: "At the LOAEL of 50 mg/kg bw/day in the two-generation study the effects were increased pup death and decreased pup body weight gain. However, the increased pup death is most likely caused by the high litter size, and the decreased pup body weight gain is likely to be due to maternal toxicity."

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subchronic

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Definitive multi generation studies on reproductive toxicity/fertility are not a standard information requirement according to REACH for the tonnage band 100 – 1000 t/a, if data on repeated dose toxicity do not indicate adverse effects on reproductive organs or tissues.

For Mecoprop-P n-octyl ester the results of a subchronic (90-days) repeated dose study (see chapter repeated dose toxicity) did not show any adverse effects on reproductive organs or tissues in males and females, therefore no definite generation study is triggered.

 

However, a two-generation reproductive toxicity study is available for Mecoprop-P acid (MCPP-P acid), which is the hydrolysis product of Mecoprop-P n-octyl ester, and is thus included in this chapter.

A comparison of the data from repeated dose studies show that for systemic toxicity the compounds have very similar toxicological profiles with respect to dose level and target organ. This is based on the fact, that Mecoprop-P n-octyl ester is in vivo rapidly metabolised to Mecoprop-P acid (MCPP-P acid) and the corresponding alcohol, and thus systemic toxicity is finally determined by the same species.

A full and elaborated justification for the read across is attached to this endpoint summary.

Consequently, there is no trigger for further studies on reproductive toxicity.

 

For Mecoprop-P studies of the racemate (Mecoprop) are relevant, and thus included in this chapter. The relevance was confirmed by the Danish Environmental Protection Agency (Danish EPA), who already assessed toxicity to reproduction for Mecoprop-P (Danish EPA, Mecoprop-P, EU Review Programme on active substances in Plant Protection Products, Scientific Evaluation and Assessment, Draft December 1998 (Volume 3, Annex B) and Addendum II July 2002):

“The effects of mecoprop-P on reproduction toxicity have been investigated in teratogenicity studies with rats and rabbits (full study reports) and in mice (scientific article including both mecoprop-P and mecoprop). Further studies with mecoprop racemic form were submitted including a two-generation study in rats and teratogenicity studies in rats and rabbits (all full study reports). Additional studies in the form of scientific articles were included in the dossier.”

 

Overview of NOAEL's and LOAEL's for reliable reproduction toxicity studies submitted with the Mecoprop-P dossier

 

Study type and substance	Species	NOAEL	LOAEL	Reference
Two-generation Mecoprop (racemic)	Wistar rat	Maternal: 100 ppm diet Foetal: 100 ppm diet equivalent to10 mg/kg bw/day	Maternal: 500 ppm diet Foetal: 500 ppm diet equivalent to50 mg/kg bw/day	Hellwig 1992

 

"At the LOAEL of 50 mg/kg bw/day in the two-generation study the effects were increased pup death and decreased pup body weight gain. However, the increased pup death is most likely caused by the high litter size, and the decreased pup body weight gain is likely to be due to maternal toxicity."

 

"Overall, the results do not suggest any classification."

Justification for selection of Effect on fertility via oral route:
Based on read-across only one study available

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

According to regulation (EC) No 1907/2006 (REACH), Annex XI 1.5 there is an option to fulfill data gaps with data of reference substance(s) by read-across. For Mecoprop-P n-octyl ester such a read-across is applied for developmental toxicity/terratogenicity with Mecoprop-P acid (MCPP-P acid), which is the hydrolysis product of Mecoprop-P n-octyl ester.

The read-across is justified, because a comparison of the available data on systemic repeated dose toxicity show for Mecoprop-P n-octyl ester and its hydrolysis product Mecoprop-P acid (MCPP-P acid), that both compounds have similar toxicological profiles with respect to dose level and target organ. This is based on the fact, that Mecoprop-P n-octyl ester is in vivo rapidly hydrolysed to Mecoprop-P acid (MCPP-P acid) and the corresponding alcohol n-octanol (CAS-No. 111-87-5), and thus systemic toxicity is finally determined by the same species.

A full and elaborated justification for the read across is attached to this endpoint summary.

No indications for developmental toxicity were reported for n-Octanol (MAK Value Documentation, 2003; The MAK Collection for Occupational Health and Safety, http://onlinelibrary.wiley.com/book/10.1002/3527600418/topics).

For Mecoprop-P both studies of the racemate (Mecoprop) and of the R-isomer (Mecoprop-P) are relevant, and thus included in this chapter.

The relevance was confirmed by the Danish Environmental Protection Agency (Danish EPA), who already assessed developmental toxicity/teratogenicity of Mecoprop-P (Danish EPA, Mecoprop-P, EU Review Programme on active substances in Plant Protection Products, Scientific Evaluation and Assessment, Draft December 1998 (Volume 3, Annex B) and Addendum II July 2002):

“The effects of mecoprop-P on reproduction toxicity have been investigated in teratogenicity studies with rats and rabbits (full study reports) and in mice (scientific article including both mecoprop-P and mecoprop). Further studies with mecoprop racemic form were submitted including a two-generation study in rats and teratogenicity studies in rats and rabbits (all full study reports). Additional studies in the form of scientific articles were included in the dossier.”

 

Overview of NOAEL's and LOAEL's for reliable developmental toxicity studies with Mecoprop-P

Study type and substance	Species	NOAEL in mg/kg bw/day	LOAEL in mg/kg bw/day	Reference
Teratogenicity Mecoprop (racemic)	CD rat	Maternal: 50 Foetal: 50	Maternal: 125 Foetal: 125	Irvine 1980
Teratogenicity Mecoprop-P (R-isomer)	Wistar rat	Maternal: 50 Foetal: 50	Maternal: 100 Foetal: 100	Hellwig 1993
Teratogenicity Mecoprop-P (R-isomer)	Himalayan rabbit	Maternal: 50 Foetal: 20	Maternal: >50 Foetal: 50	Hellwig 1993
Teratogenicity Mecoprop (racemic) and Mecoprop-P (R-isomer)	NMRI mice	Maternal: 500* Foetal: 200** both substances	Maternal: 700 (only found for Mecoprop) Foetal: 300 (both substances)	Roll 1983
Teratogenicity Mecoprop (racemic)	Dutch belted rabbit	Maternal: 75 Foetal: 75	Maternal: >75 Foetal: >75	Irvine 1990

 

"In the teratogenicity studies the NOAEL's ranged from 20 to 200 mg/kg bw/day for foetal toxicity and from 20 - 500 mg/kg bw/day for maternal toxicity. The foetal effects seen in various studies were increased number of late resorptions, reduced crown/rump length, delayed ossification, and reduced foetal weight.”

 

“Overall, the results do not suggest any classification.”

Justification for selection of Effect on developmental toxicity: via oral route:
No study was selected here, since all available studies on developmental toxicity on rats and on rabbits were relevant for assessment.

Justification for classification or non-classification

No classification is warranted for reproductive toxicity according to Regulation (EC) No 1272/2008, Annex I.