Dioctyl maleate, branched

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

Study conducted outside the EU over 10 years before the EU cosmetic testing ban came into effect.

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

Full read-across information is appended.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The source substance and target substances behave in substantially similar ways in water, and are considered to be functionally similar when inside the body. The target substance has a higher molecular weight and lower dermal absorption coefficient, and is therefore considered to be less likely to enter the body through the skin or via oral absorption. The potential for acute dermal toxicity, repeated dose toxicity and toxicity to reproduction is therefore lower in the target substance than the source substance.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Both substances are esters, with the carbonyl (C=O) part of each ester separated by 2 carbons. In addition, the two carbons are unsaturated as they share a double bond. In both cases this double bond is present in the cis geometry. The principle difference between the two substances is that the maleic anhydride is a ring structure, with the esters sharing the hydroxy group between them; whereas in the target substance there are two distinct ester components with branching chains (a methyl (odd) and a hexyl (even)).
Both substances can undergo hydrolysis to produce the same carboxylic acid as shown in the appended .pdf (Table 4). However, Maleic anhydride undergoes this process more readily as it is hygroscopic. The carboxylic acid formed is maleic acid, which can undergo hydration upon further reaction with water to produce malic acid.
The principle difference between how the source and target substances undergo hydrolysis is that one mole of maleic anhydride only produces one mole of maleic acid and no other organic species, whereas one mole of the target substance bis(1-methylheptyl) maleate produces one mole of maleic acid and two moles of 2-octanol. The 2-octanol is a branched alcohol, with an odd numbered branch (due to the methyl chain) and an even numbered branch (due to the hexyl chain).

3. ANALOGUE APPROACH JUSTIFICATION
Due to the similarities of the source and target substance with regards to chemical structure, physico-chemical properties, and Lipinski’s rule of 5, the target substance is expected to behave in a substantially similar manner in vivo.
The target substance is therefore predicted to also have a reproductive NOEL of >55 mg/kg/day after repeated oral dosing in the rat. The target substance is also predicted to show no treatment-related effects on fetal development at up to 140 mg/kg/day after repeated oral dosing in the rat. By extension, the target substance is considered not to fulfil the criteria for toxicity to reproduction under the Classification, Labelling, and Packaging (CLP) regulation (1272/2008).

4. DATA MATRIX
See appended read-across justification.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

140 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

mortality

pre and post implantation loss

Abnormalities:

no effects observed

Dose descriptor:

NOAEL

Effect level:

140 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

changes in litter size and weights

external malformations

skeletal malformations

visceral malformations

Abnormalities:

effects observed, non-treatment-related

Localisation:

external: tail

external: pelvic region

skeletal: skull

skeletal: sternum

visceral/soft tissue: musculoskeletal system

Developmental effects observed:

no

Data source

Reference

Reference Type:

publication

Title:

Teratology and Multigeneration Reproduction Studies with Maleic Anhydride in Rats

Author:

Short, R.D., Johannsen, F.R., Levinskas, G.J., Rodwell, D.E. & Schardein, J.L.

Year:

1986

Bibliographic source:

FUNDAMENTAL AND APPLIED TOXICOLOGY, Vol 7, pp. 359-366

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

Remarks:

Study published before adoption of OECD guideline.

GLP compliance:

no

Remarks:

Study published before adoption of GLP standards.

Test material

Test material information

Constituent 1

Reference substance name:

Maleic anhydride

EC Number:

203-571-6

EC Name:

Maleic anhydride

Cas Number:

108-31-6

Molecular formula:

C4H2O3

IUPAC Name:

furan-2,5-dione

Test material form:

not specified

Specific details on test material used for the study:

Maleic anhydride was supplied by Monsanto Company as white briquettes with a purity of greater than 99%

Test animals

Species:

rat

Strain:

other: CD

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, Mass.
- Age at study initiation: 12 weeks
- Weight at study initiation: F 242-244 g
- Fasting period before study: No
- Housing: Wire mesh cages or plastic cages with corn-cob bedding
- Diet (e.g. ad libitum): Purina Rodent Chow, Ralston-Purina, St. Louis, Mo. - Ad libitum
- Water (e.g. ad libitum): - Ad libitum
- Acclimation period: 10 days

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

Briquettes of maleic anhydride were finely ground with a mortar and pestle and suspended in corn oil with the aid of a tissue homogenizer. All doses were prepared daily in corn oil in order to minimize problems with stability. A 1% (w:v) concentration was used to administer all doses. Rats (25 mated females/group) were treated orally with 30, 90, or 140 mg/kg/day of maleic anhydride. Mated females in the control group were treated in a similar manner with 14 ml/kg of corn oil.

Analytical verification of doses or concentrations:

no

Details on mating procedure:

One male and one female were housed together for mating. The day of mating was determined by daily inspection for a copulatory plug or a sperm-positive vaginal smear. This day was designated Day O of gestation.

Duration of treatment / exposure:

Day 6 through Day 15 of gestation.

Frequency of treatment:

Daily

Duration of test:

To day 20 of gestation.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

30 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

90 mg/kg bw/day (actual dose received)

Doses / concentrations 4

Dose / conc.:

140 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

25 mated females

Examinations

Maternal examinations:

Body weights were recorded at intervals during gestation.

Fetal examinations:

All fetuses were weighed and examined for external abnormalities. Approximately one-third of the fetuses were placed in Bouin's fixative and examined for soft tissue abnormalities (Wilson, 1965). The remaining fetuses were fixed in alcohol, cleared with potassium hydroxide, stained with Alizarin Red S (Dawson, 1926), and examined for skeletal abnormalities.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Description (incidence and severity):

The general appearance and behavior of rats were not altered by treatment.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

While one adult died in each of the experimental groups, the overall survival in these groups was 96% (Table 1).

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Dams in the experimental groups either failed to gain weight or lost weight between Days 6 and 9 of gestation (Table 1). However, this effect was reversible, and there were no statistically significant effects on body weight at any of the times examined.

Maternal developmental toxicity

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

There was no evidence of postimplantation loss (Table 1).

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

140 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

mortality

pre and post implantation loss

Maternal abnormalities

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Compared with concurrent controls, fetal body weights were slightly reduced for all test groups, but the reductions were statistically significant only in the low- and high-dose groups. However, this is not considered to be compound-related, because fetal weights for concurrent control and all treated groups were slightly greater than the values for historical controls.

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

Dams from all test groups produced normal-sized litters (Table 1).

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

The fetal variations were comparable both in type and frequency in the control and treated groups.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

The fetal variations were comparable both in type and frequency in the control and treated groups.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

The fetal variations were comparable both in type and frequency in the control and treated groups.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

140 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

changes in litter size and weights

external malformations

skeletal malformations

visceral malformations

Fetal abnormalities

Abnormalities:

effects observed, non-treatment-related

Localisation:

external: tail

external: pelvic region

skeletal: skull

skeletal: sternum

visceral/soft tissue: musculoskeletal system

Overall developmental toxicity

Developmental effects observed:

no

Any other information on results incl. tables

TABLE 1. MATERNAL AND FETAL DATA FROM RATS TREATED WITH MALEIC ANHYDRIDE DURING GESTATION

	Maleic anhydride (mg/kg/day)
	0	30	90	140
Number treated	25	25	25	25
Pregnant	23	24	20	21
Alive	23	23	19	21
Nonpregnant	2	1	5	4
Alive	2	1	5	3
Body weight (g)
Day 0	242	244	242	243
Day 6	261	264	266	264
Day 9	272	264	264	258
Day 12	293	286	283	282
Day 15	315	302	303	298
Day 20	397	377	385	378
Implants/dam	13.3(14)a	13.4(14)	13.2(13)	13.5(14)
Viable fetuses/dam	12.6(13)	12.7(13)	12.5(13)	12.7(13)
Resorptions/dam	0.8 (0)	0.7(0)	0.7(1)	0.8 (0)
Fetal weight (g)	4.0(3.8)	3.7(3.8)b	3.8(3.8)	3.7 (3.6)b

a Mean (median).

b Mean significantly different from control. The historical control value for fetal weight was 3.6 g for 1774 fetuses

TABLE 2. OBSERVATIONS OF FETUSES FROM RATS TREATED WITH MALEIC ANHYDRIDE DURING GESTATION

	Maleic anhydride (mg/kg/day)
	0	30	90	140
Number examined
Litters	23	23	19	23
Fetuses
External	289	292	237	267
Skeletal	189	190	155	174
Soft tissue	100	102	82	93
Malformations
Short tail		1 (1)a
Omphalocele				1 (1)
Spherical enlargement on ribs	1 (1)
Fused sternebrae		1 (1)
Bent ribs				1 (1)
Multiple anomalies				1 (1)b
Total with above malformations	1 (1)	2 (2)	0 (0)	3 (3)
Variations
Rudimentary 14th rib(s)	51 (17)	62 (20)	46 (16)	37 (13)
Full 14th rib(s)	1 (1)	2 (2)	3 (3)	1 (1)
27 presacral vertebrae		5 (4)	2 (1)	2 (2)
Sternebrae 5 and/or 6 unossified	12 (9)	16 (7)	12 (6)	20 (12)
7th cervical rib	3 (2)	1 (1)	1 (1)
Misaligned centra				1 (1)
Reduced ossification of skull		1 (1)		1 (1)
Hyoid unossified		5 (3)
Pubis unossified		1 (1)
Renal papillar not developed	2 (2)			1 (1)

a Number of fetuses (number of litters).

b Includes malformed humerus, stemoschisis, and ossification defects of the pubis, cervical arches, and skull

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study, it is concluded that maleic anhydride is not teratogenic.

Executive summary:

In the teratology study, pregnant rats (19-23/group) received 0, 30, 90, or 140 mg/kg/day maleic anhydride in corn oil orally from Days 6-15 of gestation and fetuses were examined for gross soft tissue and skeletaldefects. A reduced weight gain or weight loss was observed in all maleic anhydride-treated groups between Days 6 and 9; however, mean weights of all groups were within 5% of control on Days 15 and 20. No treatment-related effects on fetal development were observed.